# The Brain Glucose Metabolism Link With Dopamine Megathread



## karoloydi (Feb 18, 2010)

Heres all the studies I have compiled about the link between glucose and dopamine. (I hope this thread stays clean this time. I dont want to see it deleted again.)

*I. BRAIN GLUCOSE METABOLISM AND DOPAMINE/ANXIETY*

Anxiety Disorders - The Dopamine Connection And Why It Actually Is All In Your Head
http://www.scientificblogging.com/n...ction_and_why_it_actually_is_all_in_your_head


> *Other neuroimaging studies have shown abnormalities in glucose and oxygen consumption in the brain* (of people with SA)


http://ajp.psychiatryonline.org/cgi/...ct/158/12/2015


> Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). *D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex* in abusers and in comparison subjects.


Same relationship found in cocaine abusers:
http://lib.bioinfo.pl/pmid:8101394

Another one showing relationship between glucose metabolism and anxiety in bipolar depression:
http://lib.bioinfo.pl/pmid:19962861


> Results indicate that comorbid anxiety symptoms have specific r*egional cerebral metabolic correlates in bipolar depression* and cannot only be explained exclusively by the depressive state of the patients


http://www.sciencedirect.com/science...a8bb69af914309


> Presynaptic *dopaminergic agonists modify brain glucose metabolism *in a way similar to the neuroleptics


http://www.ncbi.nlm.nih.gov/pubmed/3157422


> D*opamine D2 receptor agents, but not dopamine D1, modify brain glucose metabolism*


Also this study shows that administration of antipsychotic medicine Haloperidol that works by reducing dopamine shows relationship between low dopamine and low cerebral glucose utilization: 
http://www.journals.elsevierhealth.c...191-6/abstract


> *The effects of haloperidol decanoate on dopamine (DA) metabolism in discrete regions of rat brain were investigated and compared with changes in local cerebral glucose utilization (LCGU). ................... LCGU on day 21 showed significant decrease in the parietal cortex, and a tendency toward decrease in the prefrontal cortex, lateral amygdala and medial thalamus compared with the controls*


http://grande.nal.usda.gov/ibids/ind...&therow=228518


> *The stimulation of D1 and D2 dopamine (DA) receptors by selective agonists produced large increases in brain glucose concentrations. D2 receptor stimulation also produced large increases in blood glucose.*


http://www.jbc.org/content/280/44/36824.full


> *Dopamine D2-like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion................Treatment with dopamine precursor l-dopa in humans suffering from Parkinson disease reduces insulin secretion upon oral glucose tolerance test (10).........Moreover, antipsychotic (neuroleptic) drugs blocking dopamine receptors may cause hyperinsulinemia (59), hypoglycemia (60), increase appetite, and obesity (61, 62) and are associated with diabetes (61, 63, 64).*


http://www.informaworld.com/smpp/146...ent=a747898680


> Our results suggest that *dopamine exerts a differential effect on glucose-induced insulin secretion through dopamine D2 receptor and it is essential for the regulation of glucose-induced insulin secretion by pancreatic islets.*


*Disruption of the dopamine d2 receptor impairs insulin secretion and causes glucose intolerance.*
http://www.ncbi.nlm.nih.gov/pubmed/20147524

*Dopamine agonist treatment ameliorates hyperglycemia,* hyperlipidemia, and the elevated basal insulin release from islets of ob/ob mice
http://www.ncbi.nlm.nih.gov/pubmed/9784590

Gender difference in relationship between anxiety-related personality traits and cerebral brain glucose metabolism.
http://www.ncbi.nlm.nih.gov/pubmed/19682867


> *HA was negatively correlated with glucose metabolism in the anterior portion of the ventromedial prefrontal cortex (vmPFC) in females but not in males.*


Cocaine and amphetamine modification of cerebral energy metabolism in vivo
http://www.springerlink.com/content/k1q19u1j055l5231/


> *Cocaine (20 mg/kg), in contrast, produced elevation of brain glucose*


Serotonin mediates rapid changes of striatal glucose and lactate metabolism after systemic 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") administration in awake rats
http://www.sciencedirect.com/scienc...serid=10&md5=46334b8f62dbd636fbfaa53cbdf97794


> *A single dose of MDMA (2-10-20 mg/kg i.v.) evoked a transient increase of interstitial glucose concentrations in striatum (139-223%) with rapid onset and of less than 2 h duration, a concomitant but more prolonged lactate increase (>187%) at the highest MDMA dose and no significant depletions of striatal serotonin. Blood glucose and lactate levels were also transiently elevated (163 and 135%) at the highest MDMA doses. The blood glucose rises were significantly related to brain glucose and brain lactate changes. The metabolic perturbations in striatum and the hyperthermic response (+1.1 °C) following systemic MDMA treatment were entirely blocked in p-chlorophenylalanine pre-treated rats, indicating that these effects are mediated by endogenous serotonin.*


Regional brain glucose metabolism: Correlations to biochemical measures and anxiety in patients with schizophrenia
http://www.sciencedirect.com/scienc...serid=10&md5=466df4a50ac74587cd5b71a231922bcd


> In all subjects, positive correlations were found between the level of anxiety and the regional glucose metabolism.


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## karoloydi (Feb 18, 2010)

*II. BRAIN GLUCOSE METABOLISM AND ADHD*

Heres my previous post about the link between glucose and ADHD:

ADHD drugs mainly work by increasing norepinephrine and dopamine.
But how does the increase of norepinephrine affect ADHD? My theory is that ADHD is caused by insufficient glucose metabolism in the brain.

http://endo.endojournals.org/cgi/con...do;144/10/4427


> Norepinephrine (NE) and epinephrine (Epi) help maintain normal blood glucose levels by stimulating glucagon release, glycogenolysis, and food consumption, and by inhibiting insulin release.


So, by increasing noradrenalin you help more glucose to go to the brain.
We all know that glucose is like fuel for the brain. Without glucose the brain cant function properly. You can check wikipedia for symptoms of hypoglycemia and you ll see that it matches the symptoms of ADHD:
http://en.wikipedia.org/wiki/Hypoglycemia

Read this study and you ll see what the effects of low sugar have on these students after a metally demanding task:



> Roy Baumeister, a psychologist at Florida State University, had subjects perform a mentally taxing task - watching a video while being careful to ignore random words scrolling across the bottom of the screen. (Apparently, it takes quite a bit of concentration to NOT look at the scrolling words.) Then, the subjects were given a drink of lemonade and asked to perform another cognitively demanding task, choose an apartment based on descriptions of various options.
> The catch was that some subjects drank lemonade made with real sugar, and others had lemonade made with Splenda, a sugar substitute without nutritional value. The performance differences on the apartment task were surprising.
> *Baumeister reported that the students who received the sugar-free lemonade were significantly more likely to choose impulsively and make poor decisions on the apartment task. He attributed this to the exhaustion of the prefrontal cortex in all subjects.* The subjects who got the sugar were able to better restore function to that area of the brain. (Fifteen minutes was allowed to elapse after consuming the lemonade to permit the sugar to reach the brain.)
> According to Jonah Lehrer, who reports on this work in How We Decide,
> This research can also help explain why we get cranky when we're hungry and tired: *the brain is less able to suppress the negative emotions sparked by small annoyances. A bad mood is really just a run-down prefrontal cortex.*


Studies suggest that the frontal/prefrontal cortex works more slowly in children with ADHD than in other children. I suggest that this is due to low glucose in the brain. Thats why by increasing norepinephrine you reduce the symptoms of ADHD. Cause by increasing norepinephrine you also increase the glucose in the brain.

http://www.ncbi.nlm.nih.gov/pubmed/8489322


> Global or absolute measures of metabolism did not statistically differ between groups, although hyperactive girls had a 17.6% lower absolute brain metabolism than normal girls. As compared with the values for the controls, *normalized glucose metabolism was significantly reduced in six of 60 specific regions of the brain, including an area of the left anterior frontal lobe (P < .05). Lower metabolism in that specific region of the left anterior frontal lobe was significantly inversely correlated with measures of symptom severity* (P < .001-.009, r = -.56 to -.67).


This is what I ve found about the left frontal lobe here:
http://www.neuroskills.com/tbi/bfrontal.shtml


> The left frontal lobe is involved in controlling language related movement, whereas the right frontal lobe plays a role in non-verbal abilities.


This author believes that there could be a link between ADHD and glucose as well:
http://www.ncbi.nlm.nih.gov/pubmed/11513813


> Quote:
> *At least some forms of ADHD may be viewed as cortical, energy-deficit syndromes secondary to catecholamine-mediated hypofunctionality of astrocyte glucose and glycogen metabolism*, which provides activity-dependent energy to cortical neurons. Several tests of this hypothesis are proposed.


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## karoloydi (Feb 18, 2010)

*III. BRAIN GLUCOSE METABOLISM AND DEPRESSION*

http://archpsyc.ama-assn.org/cgi/con...tract/57/8/787
Reduced Brain Norepinephrine and Dopamine Release in Treatment-Refractory Depressive Illness
Evidence in Support of the Catecholamine Hypothesis of Mood Disorders


> Background The etiology of depressive illness has been linked with brain monoaminergic neuronal dysfunction, yet the development of sensitive markers of endogenous depression has proven difficult.
> 
> Methods Using catheters placed in an internal jugular vein, we estimated the release of brain monoamine neurotransmitters in 19 healthy volunteers and in 9 patients with nonbipolar depressive illness refractory to medication at rest and following intravenous desipramine hydrochloride. Venoarterial plasma concentration gradients were used to quantify the amount of neurotransmitters stemming from the brain. Cerebral oxidative metabolism was assessed concurrently from measurements of oxygen and carbon dioxide gas exchange via the process of regional indirect calorimetry.
> 
> ...


I think that other energy source is lactic acid, but I am not 100% sure.

Relationship between personality trait and regional cerebral glucose metabolism assessed with positron emission tomography
http://www.ncbi.nlm.nih.gov/pubmed/12270587


> There have been no studies systematically investigating relationships between biogenetic temperament dimensions and patterns of brain glucose metabolism. Nineteen healthy subjects were evaluated regarding the biogenetic temperament using Cloninger's Temperament and Character Inventory (TCI). In addition, [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) was used to measure regional brain glucose metabolism. Voxel-based correlation analysis was used to test correlations between regional brain glucose metabolism and scores on the TCI. We identified that each temperament dimension, such as Novelty Seeking, Harm Avoidance, and Reward Dependence, was significantly correlated with specific brain regions. The majority of correlations were observed in the areas of paralimbic regions and temporal lobes. The current study provides evidence linking each biogenetic temperament dimension with specific brain areas and provides a promising base for future personality research.


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## karoloydi (Feb 18, 2010)

*IV. CORTISOL, GLUCOSE AND SOCIAL ANXIETY*

If we take a leap of faith from the previous studies above, we could also argue that the anti anxiety effects of cortisol could also be due to its ability to increase glucose.



> Cortisol counteracts insulin, contributing to hyperglycemia by stimulation of hepatic gluconeogenesis[5] and inhibition of the peripheral utilization of glucose[5] by decreasing the translocation of glucose transporters to the cell membrane,[6] specially GLUT4.[7] However cortisol increases glycogen synthesis (glycogenesis) in the liver.[8] Permissive effect of cortisol on insulin action on liver glycogenesis is observed in hepatocyte culture in laboratory, although the mechanism is unknown.





> *Researchers from the University of Zurich are suggesting that a dose of the stress hormone cortisol may help people overcome phobias.*
> 
> They have come up with a pill which is based on cortisol. Cortisol impairs the retrieval of memories, and people forget what they are fearful of.
> Working on this principle the researchers were curious to see if people with a phobia such as fear of spiders, when given a dose of the hormone before exposure to a spider, or their own personal phobia trigger, would be helped.
> ...


I also found that aspergers syndrome, a condition that causes similar symptoms as social anxiety is linked with low cortisol.

http://content.karger.com/produktedb...file=000106056


> Plasma prolactin levels are sensitive to dopamine and serotonin function, and fatigue. Low cortisol, dopamine and/or serotonin may be involved in burnout and detachment. Methods: In this double-blind within-subject study, we treated 9 female burnout subjects and 9 controls with 35 mg cortisol and placebo orally. We measured state affect and plasma prolactin, oxytocin, cortisol and adrenocorticotropic hormone levels, and administered an attachment questionnaire. Results: The burnout subjects displayed an extreme distribution of basal prolactin levels, displaying higher or lower levels compared to the controls. The low prolactin burnouts had profoundly low attachment scores and tended to have low oxytocin levels. The high prolactin burnout subjects tended to show cortisol-induced decreased prolactin and fatigue, and increased vigor. Conclusion: *Results are consistent with the hypothesis that burnout subjects are either characterized by low serotonergic function or by low dopaminergic function, and that the latter group benefits from cortisol replacement*. These preliminary results suggest that differentiating between two syndromes may resolve inconsistencies in research on burnout, and be necessary for selecting the right treatment strategy.


This is from one article I ve read (its been talking about new experiences, like sky diving):
http://health.usnews.com/usnews/heal...9/29book_2.htm


> But with dopamine in the striatum, cortisol interacts synergistically. Novelty releases dopamine, stress releases cortisol, and when they come together they create an intense feeling of satisfaction.


http://www.ehow.com/facts_5798168_co...-learning.html


> Cortisol is needed for the hypothalamus to be fully alert. *When cortisol is produced, it helps stimulate dopamine production in the brain.* Helped by cortisol, dopamine levels typically remain elevated until midday. This is why most schools are open from early morning until late afternoon, when dopamine levels are at their peak.


http://www.nature.com/npp/journal/v3.../1300667a.html


> Findings showed that *cortisol levels were positively associated with AMPH-induced DA release in the left ventral striatum (LVS) and the dorsal putamen.* Subjects with higher cortisol responses to AMPH also reported more positive subjective drug effects than subjects with lower cortisol responses


http://jds.fass.org/cgi/content/abstract/89/6/2051


> Our results indicated that a dopamine antagonist increased cortisol, suggesting that endogenous *dopamine, at least in part, regulates cortisol and prolactin secretion.*


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## karoloydi (Feb 18, 2010)

*V. ANXIETY AND LACTIC ACID*

My theory is that the brain of people with social anxiety used higher levels of lactic acid as an energy source due to problems with glucose metabolism.
(Theres also a thread in mind and muscle forums about a guy that took a drug that reduces lactic acid. Will dig it up later)

*This study is quite indicate of what kind of energy sources the brain is using and their order of importance with glucose first, lactate second, glutamine and glutamate third and aspartate last*:

Neurochemical changes in the developing rat hippocampus during prolonged hypoglycemia.
http://www.ncbi.nlm.nih.gov/pubmed/20477939


> J. Neurochem. (2010) 10.1111/j.1471-4159.2010.06797.x Abstract Hypoglycemia is common during development and is associated with the risk of neurodevelopmental deficits in human infants. The effects of hypoglycemia on the developing hippocampus are poorly understood. The sequential changes in energy substrates, amino acids and phosphocreatine were measured from the hippocampus during 180 min of insulin-induced hypoglycemia (blood glucose < 2.5 mmol/L) in 14-day-old rats using in vivo(1)H NMR spectroscopy. Hypoglycemia resulted in neuroglycopenia (brain glucose < 0.5 mumol/g). However, the phosphocreatine/creatine (PCr/Cr) ratio was maintained in the physiological range until approximately 150 min of hypoglycemia, indicating that energy supply was sufficient to meet the energy demands. Lactate concentration decreased soon after the onset of neuroglycopenia. Beyond 60 min, glutamine and glutamate became the major energy substrates. A precipitous decrease in the PCr/Cr ratio, indicative of impending energy failure occurred only after significant depletion of these amino acids. Once glutamate and glutamine were significantly exhausted, aspartate became the final energy source. N-acetylaspartate concentration remained unaltered, suggesting preservation of neuronal/mitochondrial integrity during hypoglycemia. Correction of hypoglycemia normalized the PCr/Cr ratio and partially restored the amino acids to pre-hypoglycemia levels. Compensatory neurochemical changes maintain energy homeostasis during prolonged hypoglycemia in the developing hippocampus.


Comparison of glucose and lactate as substrates during NMDA-induced activation of hippocampal slices.
http://www.ncbi.nlm.nih.gov/pubmed/11223002


> It has been postulated that lactate released from astrocytes may be the preferred metabolic substrate for neurons, particularly during intense neuronal activity (the astrocyte-neuron lactate shuttle hypothesis). We examined this hypothesis by exposing rat hippocampal slices to artificial cerebrospinal fluid containing either glucose or lactate and either N-methyl-D-aspartate, which activates neurons without stimulating astrocytic glucose uptake, or alpha-cyano-4-hydroxycinnamate, which blocks monocarboxylate transport across plasma and mitochondrial membranes. When exposed to N-methyl-D-aspartate, slices lost synaptic transmission and K+ homeostasis more slowly in glucose-containing artificial cerebrospinal fluid than in lactate-containing artificial cerebrospinal fluid. After N-methyl-D-aspartate exposure, slices recovered synaptic transmission more completely in glucose. T*hese results suggest that hippocampal neurons can use glucose more effectively than lactate when energy demand is high.* In experiments with alpha-cyano-4-hydroxycinnamate, 500 microM alpha-cyano-4-hydroxycinnamate caused loss of K+ homeostasis and synaptic transmission in hippocampal slices during normoxia. When 200 microM alpha-cyano-4-hydroxycinnamate was used, synaptic activity and intracellular pH in slices decreased significantly during normoxia. These results suggest that alpha-cyano-4-hydroxycinnamate may have blocked mitochondrial oxidative metabolism along with lactate transport. Thus, studies using alpha-cyano-4-hydroxycinnamate to demonstrate the presence of a lactate shuttle in the brain tissue may need reevaluation. Our findings, together with observations in the literature that (1) glucose is available to neurons during activation, (2) heightened energy demand rapidly activates glycolysis in neurons, and (3) activation of glycolysis suppresses lactate utilization, suggests that glucose is the primary substrate for neurons during neuronal activation and do not support the astrocyte-neuron lactate shuttle hypothesis.


The Lactic Acid Response to Alkalosis in Panic Disorder
http://neuro.psychiatryonline.org/cgi/content/full/13/1/22


> Panic patients consistently show exaggerated lactic acid response to alkalosis, whether produced by hyperventilation or by sodium lactate infusion. Understanding why this occurs may provide important clues to the pathogenesis of panic disorder. Although brain hypoxia from excessive hypocapnia-induced cerebral vasoconstriction is often cited as the mechanism of elevated brain lactic acid in panic disorder, studies of brain metabolism show that hypocapnia rarely leads to brain hypoxia. Increased lactic acid production is a normal response to intracellular alkalosis and to intracellular cyclic AMP. Thus, other possible mechanisms of the exaggerated lactic acid response in panic disorder include a disturbance of mechanisms regulating intracellular pH and factors increasing intracellular cyclic AMP. Both mechanisms are consistent with the suffocation false alarm theory of panic disorder. This review suggests a theoretical framework for future magnetic resonance spectroscopy studies that can test some of the predictions of these competing models.


Anxiety and the Effects of Sodium Lactate Assessed Clinically and Physiologically
http://bjp.rcpsych.org/cgi/content/abstract/119/549/129


> 1. *Pitts and McClure reported that anxiety attacks could be produced in anxious patients by the infusion of sodium lactate*, and they formulated a new theory to explain how this was achieved. To test their findings, 20 patients suffering from anxiety neurosis and 10 normal controls were given an intravenous infusion of saline followed by one of sodium lactate, and 12 minutes after the infusion ended they were stressed by mental arithmetic. Throughout the procedure, psychological and physiological arousal were monitored by observer and self-ratings of anxiety, forearm blood flow and heart rate. All these measures increased significantly when the intravenous cannula was inserted.
> 
> 2. *Eighty-five per cent of the patients experienced an anxiety attack during or after the sodium lactate infusion, as compared with only 5 per cent during normal saline*. The number of anxiety symptoms and mean observer and self-ratings of anxiety, forearm blood flow and heart rate were higher during the lactate than during the saline infusion.
> 
> ...


A Comparison of Sodium Bicarbonate and Sodium Lactate Infusion in the Induction of Panic Attacks
http://archpsyc.ama-assn.org/cgi/content/abstract/46/2/145


> *Thirteen of 22 subjects panicked in response to lactate* ..........*lactate may be a more potent producer of anxiety than bicarbonate*.


Metabolic effects of low-dose dopamine infusion in normal volunteers.
http://www.ncbi.nlm.nih.gov/pubmed/2176947


> *The plasma noradrenaline concentration was 74 and 230% and the blood glucose concentration was 21 and 36% higher than control values at 5 and 10 micrograms of dopamine min-1 kg-1, respectively (P less than 0.01)*.......*The respiratory exchange ratio and the plasma lactate concentration were the same*.........*Dopamine at low doses has metabolic effects. It increases the blood glucose concentration and the circulating noradrenaline level at an infusion rate of 5 micrograms min-1 kg-1. It increases energy expenditure*


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## karoloydi (Feb 18, 2010)

*VI. NMDA AND BRAIN GLUCOSE/LACTIC ACID*

I have a theory that part of the mechanism of tolerance prevention is due to their effect in brain glucose and lactic acid.

I also found this interesting relationship between lactate and glutamate:

Lactate production and neurotransmitters; evidence from microdialysis studies.
http://www.ncbi.nlm.nih.gov/pubmed/18502489


> Recent studies have found that lactate metabolism plays a significant role in energy supply during acute neural activation in the brain. We will review evidence from microdialysis studies for a relationship between neurotransmitters and lactate production, as revealed in studies of the effects of psychotropic drugs on stress-induced enhancement of extracellular lactate concentrations. G*lutamate enhances stress-induced lactate production via activation of N-methyl-D-asparate receptors, and is affected by uptake of glutamate through glutamate transporters.* Findings from microdialysis studies suggest that major neurotransmitters, including norepinephrine, dopamine, serotonin, and GABA (via benzodiazepine-receptors) affect lactate production, depending on brain areas, especially during stress. *Among these neurotransmitters, glutamate may principally contribute to the regulation of lactate production*, with other neurotransmitter systems affecting the extracellular lactate levels in a glutamate-mediated manner. The role for anaerobic metabolism in the supply of energy, as represented by lactate dynamics, deserves further clarification. Monitoring with intracerebral microdialysis is a reliable method for this purpose. Research into this area is likely to provide a novel insight into the mode of action of psychotropic drugs, and the pathophysiology of some of the stress-related mental disorders as well.


Glycolysis regulates the induction of lactate utilization for synaptic potentials after hypoxia in the granule cell of guinea pig hippocampus.
http://www.ncbi.nlm.nih.gov/pubmed/15567484


> Lactate is considered an alternative substrate that is capable of replacing glucose in maintaining synaptic function in adult neurons. *But, we found recently that lactate could be utilized for maintenance of synaptic potentials only after the activation of NMDA and voltage-dependent-calcium channel during glucose deprivation.* To clarify more on the relationship between glycolysis and induction of lactate utilization, we tested lower concentration of glucose with hypoxia to induce a relative shortage of anaerobic energy production. Population spikes are not maintained with lactate following hypoxia in 10 mM glucose medium, but are maintained at their original levels with lactate after exposure to hypoxia in lower concentration (5 mM) of glucose. Hypothermia during low glucose-hypoxia, bath application of the NMDA channel blocker and the voltage-sensitive calcium channel blocker, as well as the omission of extracellular calcium prevented the induction of the lactate-supported population spikes. ATP levels in the tissue slices are relatively preserved in the conditions that block the induction of lactate-supported population spikes. From these observations, we propose that the energy source for maintenance of synaptic function in adult neuron changes from adult form (glucose alone) to immature one (glucose and/or lactate) after short of glucose supply.


Pre-ischemic treatment with memantine reversed the neurochemical and behavioural parameters but not energy metabolites in middle cerebral artery occluded rats.
http://www.ncbi.nlm.nih.gov/pubmed/19463256


> In the present study, memantine (MN) an uncompetitive N-methyl-D-aspartate (NMDA) open channel blocker has been investigated for its suitable therapeutic time-window on the basis of its influence on behavioural and biochemical changes in rats subjected to transient focal ischemia. MN (20 mg/kg, ip) was administered at pre, during and post ischemic state and the extent of neuroprotection was compared to ascertain its therapeutic time-window in stroke treatment. Neuroprotective effect was assessed by measuring glutamate, glutamine synthetase, glutathione, Na+K+ATPase, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD), lactate and pyruvate levels. *Middle cerebral artery occlusion produced neurological deficits, anxiogenic behaviour*, histological changes, increased glutamate levels along with depletion of Na+K+ATPase, energy stores such as ATP, NAD, lactate, and antioxidant glutathione. *MN significantly restored glutamate, glutamine synthetase, Na+K+ATPase and lactate levels on preischemic administration*. In addition, MN reversed the altered neurological and behavioural paradigms significantly and prevented the neurodegeneration on preischemic treatment. However, it failed to exert any effect on energy metabolite (ATP and NAD) levels irrespective of the treatment phase. Based on the present data, it is summarized that the suitable therapeutic time window of MN is preischemic phase in stroke and it possesses only a subjective role in reversing ischemic brain biochemical alterations preferentially in favor of neuronal homeostasis.


*Neuronal glucose but not lactate utilization is positively correlated with NMDA-induced neurotransmission* and fluctuations in cytosolic Ca2+ levels.
http://www.ncbi.nlm.nih.gov/pubmed/19393013


> Although the brain utilizes glucose for energy production, individual brain cells may to some extent utilize substrates derived from glucose. Thus, it has been suggested that neurons consume extracellular lactate during synaptic activity. However, the precise role of lactate for fueling neuronal activity is still poorly understood. *Recently, we demonstrated that glucose metabolism is up-regulated in cultured glutamatergic neurons during neurotransmission whereas that of lactate is not. Here, we show that utilization of glucose but not lactate correlates with NMDA-induced neurotransmitter glutamate release in cultured cerebellar neurons from mice.* Pulses of NMDA at 30, 100, and 300 microM, leading to a progressive increase in both cytosolic [Ca2+] and release of glutamate, increased uptake and metabolism of glucose but not that of lactate as evidenced by mass spectrometric measurement of 13C incorporation into intracellular glutamate. In this manuscript, a cascade of events for the preferential neuronal utilization of glucose during neurotransmission is suggested and discussed in relation to our current understanding of neuronal energy metabolism.


Functional significance of brain glycogen in sustaining glutamatergic neurotransmission.
http://www.ncbi.nlm.nih.gov/pubmed/19393012


> The involvement of brain glycogen in sustaining neuronal activity has previously been demonstrated. However, to what extent energy derived from glycogen is consumed by astrocytes themselves or is transferred to the neurons in the form of lactate for oxidative metabolism to proceed is at present unclear. The significance of glycogen in fueling glutamate uptake into astrocytes was specifically addressed in cultured astrocytes. Moreover, the objective was to elucidate whether glycogen derived energy is important for maintaining glutamatergic neurotransmission, induced by repetitive exposure to NMDA in co-cultures of cerebellar neurons and astrocytes. In the astrocytes it was shown that uptake of the glutamate analogue D-[3H]aspartate was impaired when glycogen degradation was inhibited irrespective of the presence of glucose, signifying that energy derived from glycogen degradation is important for the astrocytic compartment. By inhibiting glycogen degradation in co-cultures it was evident that glycogen provides energy to sustain glutamatergic neurotransmission, i.e. release and uptake of glutamate. The relocation of glycogen derived lactate to the neuronal compartment was investigated by employing d-lactate, a competitive substrate for the monocarboxylate transporters. Neurotransmitter release was affected by the presence of d-lactate indicating that glycogen derived energy is important not only in the astrocytic but also in the neuronal compartment.


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## karoloydi (Feb 18, 2010)

*VII. LINK BETWEEN LACTIC ACID AND ADHD*

Catecholamine response to exercise in children with attention deficit hyperactivity disorder.
http://www.ncbi.nlm.nih.gov/pubmed?term=at...correctspelling


> The objective of this study was to examine differences in catecholamine (CA) response to exercise between children who had received a diagnosis of attention-deficit/hyperactivity disorder (ADHD) and age- and gender-matched controls. On the basis of the notion of a CA dysfunction in ADHD, we reasoned that the normal robust increase in circulating CA seen in response to exercise would be blunted in children with ADHD. To test this, we recruited 10 treatment-naïve children with newly diagnosed ADHD and 8 age-matched controls (all male) and measured CA response to an exercise test in which the work was scaled to each subject's physical capability. After exercise, epinephrine and norepinephrine increased in both control and ADHD subjects (p = 0.006 and p = 0.002, respectively), but the responses were substantially blunted in the ADHD group (p = 0.018) even though the work performed did not differ from controls. Circulating dopamine increased significantly in the control subjects (p < 0.016), but no increase was noted in the subjects with ADHD. *Finally, a significant attenuation in the lactate response to exercise was found in ADHD (between groups, p < 0.005).* Our data suggest that CA excretion after exercise challenges in children with ADHD is deficient. This deficiency can be detected using a minimally invasive, nonpharmacologic challenge.


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## karoloydi (Feb 18, 2010)

*VIII. LINK BETWEEN ANXIETY AND N ACETYL ASPARTATE*

To continue with the theme that the brain uses an alternative energy source due to poor glucose metabolism, I found another one:

This article shows that N Acetyl Aspartate is the mostly eleveted chemical in the brain during anxiety (even more than lactate).

Anxiety in healthy humans is associated with orbital frontal chemistry.
http://www.ncbi.nlm.nih.gov/pubmed/11032381



> The present study examines relationships between regional brain chemistry (as identified by localized in vivo three-dimensional single-voxel proton magnetic resonance spectroscopy (1H-MRS) and anxiety (as measured by the State-Trait Anxiety Inventory) in 16 healthy subjects. The relative concentrations of N-Acetyl aspartate, choline, glutamate, glutamine, gamma-aminobutyric acid, inositol, glucose and lactate were measured relative to creatine within six 8-cm3 brain voxels localized to: thalamus, cingulate, insula, sensorimotor, dorsolateral prefrontal, and orbital frontal cortices (OFC) in the left hemisphere. Analysis of variance, across brain regions, chemicals, and high and low anxiety groups, showed a relationship between anxiety and chemical composition of OFC, with high anxiety subjects demonstrating 32% increase in overall chemical concentrations within OFC, as compared to the lower anxiety group (F= 60.8, P < 10(-7)). Other brain regions, including cingulate, showed no detectable anxiety dependence. The combination of the state and trait anxiety was highly correlated with the concentration of OFC chemicals (r2 = 0.98), and *N-Acetyl aspartate in OFC was identified as the strongest chemical marker for anxiety* (changed by 43.2% between the two anxiety groups, F = 21.5, P = 0.000005). The results provide direct evidence that the OFC chemistry is associated with anxiety in healthy humans. The method can be used as a neuroimaging/behavioral tool for documentation of OFC chemistry changes in relation to anxiety per se and anxiety disorders. The presented relationship between regional brain chemistry and anxiety reflects the functional/behavioral state of the brain, pointing to possible mechanisms of the neurobiology of anxiety.


This too shows relationship between anxiety and N Acetyl Aspartate:

Chemical mapping of anxiety in the brain of healthy humans: an in vivo 1H-MRS study on the effects of sex, age, and brain region.
http://www.ncbi.nlm.nih.gov/pubmed/11144755


> We recently presented results in an in vivo study of human brain chemistry in 'physiologic' anxiety, i.e., the anxiety of normal everyday life. Normal subjects with high anxiety demonstrated increased concentration of chemicals in orbital frontal cortex (OFC) as compared to lower anxiety. In a separate study of aging we demonstrated a decrease of total chemical concentration in OFC of middle-aged subjects, as compared with younger age. This brain region also showed gender dependence; men demonstrating decreased chemical concentration compared to women. We hypothesized that these sex- and age-dependent differences in OFC chemistry changes are a result of anxiety effects on this brain region. In the present study we examined these sex- and age-differential regional brain chemistry changes (as identified by localized in vivo proton magnetic resonance spectroscopy [1H-MRS]) in relation to the state-trait-anxiety (as measured by the State-Trait Anxiety Inventory) in 35 healthy subjects. The concentrations for all nine chemicals of 1H-MRS spectra were measured relative to creatine across multiple brain regions, including OFC in the left hemisphere. Analysis of variance showed anxiety-specific effects on chemical concentration changes in OFC, which were different for both sexes and age groups. Male subjects showed larger effect of anxiety on OFC chemistry as compared to females when the same sex high-anxiety subjects were compared to lower anxiety. Similarly, middle-aged subjects showed larger effect of anxiety on OFC chemistry as compared to younger age when the same age subjects with high anxiety were compared to lower anxiety. *Largest effect of anxiety on OFC chemistry was due to changes of N-Acetyl aspartate.* The results indicate that the state-trait anxiety has sex- and age-differential patterns on OFC chemistry in healthy humans, providing new information about the neurobiological roots of anxiety.


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## karoloydi (Feb 18, 2010)

I found something that gave me an idea:

Thats only a quote from google's search results summary. It doesnt appear on the abstract. Its from this article:
http://www3.interscience.wiley.com/journal/119954931/abstract


> *The effect of inadequate oxygen supply will be ;I switch
> from aerobic to anaerobic metabolism and increased lactate formation*


Then I remembered what I ve read on the other study on social anxiety:

http://www.scientificblogging.com/ne...l_in_your_head


> Other neuroimaging studies have shown *abnormalities in glucose and oxygen consumption in the brain (of people with SA)*


Could it be that because of low oxygen in brain the brain is switching to anaerobic metabolism? And that is whats causing the high lactate?
I am not sure how the switch to anaerobic metabolism leads to higher lactate. I ll look more into this. I think lactate doesnt require oxygen when used as a source of energy.

*EDIT: I THINK I AM ON TO SOMETHING:*

Brain Anaerobic Lactate Production: A Suicide Note or a Survival Kit?
http://content.karger.com/ProdukteD...oduktNr=224107&Ausgabe=225541&ArtikelNr=17330


> *Aerobic energy metabolism utilizes glucose and oxygen to satisfy all the energy needs of the adult brain*. Anaerobically, the brain switches to the significantly less efficient glycolytic pathway for its most basic energy requirements. Anaerobic glycolysis provides the adult brain with a limited amount of energy and time to maintain ion homoeostasis and other essential processes before several events occur that lead to brain cell damage and death. *Recent evidence that lactate, produced mainly in glial cells during a period of oxygen deprivation, becomes the only utilizable and thus obligatory substrate for aerobic energy metabolism upon reoxygenation is summarized here*. This evidence also supports the hypothesis that a lactate shuttle exists between glia and neurons, and emphasizes its importance in the post-ischemic survival of neurons.


This too:
Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals
http://www.jneurosci.org/cgi/content/abstract/14/8/5068


> The concentration of extracellular glucose in anesthetized rat brain was measured continuously with two types of substrate-specific microelectrodes in a number of physiological and pathological conditions. Extracellular glucose level increased in hyperglycemia and decreased in hypoglycemia, paralleling the changes in blood sugar. Increased neuronal activity and in particular spreading depression, evoked triphasic alterations in extracellular glucose concentration: an initial rapid fall was followed by an equally swift overshoot above the baseline and a subsequent return to it. Limitation in O2 supply led to a decline in extracellular content of glucose: respiration with 5% O2 reduced the level by 7-20% and that with 3% O2 by 75-85%. Decreases to undetectable concentrations were seen in ischemia despite the use of an oxygen-insensitive microglucose sensor. Restoration of oxygen supply to the brain was accompanied by increases in extracellular glucose content above the original normoxic level, which returned to baseline values after 10-15 min. In hyperglycemic animals ischemia-induced leakage of K+ was delayed while the rate of recovery to control levels after restitution of blood flow was enhanced. It is concluded that continuous monitoring of glucose with glucose-specific microelectrodes provides a new and important insight into brain energy metabolism.


In my case this could definately explain my social anxiety and ADHD. I have a condition called thalassemia. This is causing me mild anemia and my blood has lower capacity to carry oxygen because of this. Its also causing me hypoglycemia. And I have another condition called G6PD deficiency that causes problem with breaking down of carbohydrates.


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## Edwin (Jun 19, 2008)

Your last post also gave me an idea. It's possible these disorders (SAD/ADD) get progressively worse in time due to cell death caused by inefficient/disrupted use of glucose for energy. I wouldn't be surprised our dopaminergic neurons are falling like flies if these disorders are left untreated.

Interestingly, since starting DHA supplementation, which has remedied at least part of my symptoms, I've noticed a short adjustment period with day-time fatigue, baring all the symptoms of low blood sugar. This is some indirect anecdotal evidence for the usefulness of supplementing omega-3 fatty acids for these disorders.


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## crayzyMed (Nov 2, 2006)

> I wouldn't be surprised our dopaminergic neurons are falling like flies if these disorders are left untreated.


Yeah we are at a much bigger risk of developping parkinson, definatly something thats going wrong. (i beleive it was a 6 times bigger risk and half of the parkinson patients used to have social anxiety, if i recall correctly).


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## karoloydi (Feb 18, 2010)

BRAIN OXYGEN AND NEUROTRANSMITTERS

I ll also investigate brain oxygen since it looks relevant to the glucose hypothesis.

Brain dysfunction in mild to moderate hypoxia
http://www.amjmed.com/article/0002-9343(81)90834-2/abstract


> Hypoxia is commonly invoked to explain alterations in mental function, particularly in patients with cardiac or pulmonary failure. The effects of acute graded hypoxia on higher integrative functions are well documented experimentally in man. Hypoxia in experimental animal models demonstrates that the pathophysiology is complex. In mild to moderate hypoxia, in contrast to severe hypoxia and to ischemia, the supply of energy for the brain is not impaired; cerebral levels of adenosine triphosphate (ATP) and adenylate energy charge are normal. In contrast, the turnover of several neurotransmitters is altered by mild hypoxia. For example, acetylcholine synthesis is reduced proportionally to the reduction in carbohydrate oxidation. This relationship holds in vitro and with several in vivo models of hypoxia. Pharmacologic and physiologic studies in man and experimental animals are consistent with acetylcholine having an important role in mediating the cerebral effects of mild hypoxia. These observations raise the possibility that treatments directed to cholinergic or other central neurotransmitter systems may benefit patients with cerebral syndromes secondary to chronic hypoxia.


Effects of Hypoxia on the Activities of Noradrenergic and Dopaminergic Neurons in the Rat Brain
http://www3.interscience.wiley.com/journal/119490334/abstract


> The effects of hypoxia (10% O2, 90% N2) on the content, biosynthesis, and turnover of noradrenaline (NA) and 3,4-dihydroxyphenyIethylamine (dopamine, DA) in the rat brain were examined. Up to 24 h following exposure to hypoxia, NA content in the whole brain was decreased, whereas DA content remained unchanged. The accumulation of 3,4-dihydroxyphenylalanine (DOPA) after central decarboxylase inhibition was decreased. The turnover rate of DA after synthesis inhibition was markedly decreased up to 8 h and returned to the control level within 24 h. In contrast, the turnover rate of NA was all but unchanged, except for a 4-h exposure. The 2-h exposure to the hypoxic environment resulted in a significant decrease in NA content and DOPA accumulation in all brain regions tested, but no significant change was observed in DA content. The turnover rate of DA was remarkably decreased in all brain regions tested, whereas the rate of NA was slightly decreased only in the cerebral cortex and hippocampus. These results suggest that although hypoxia decreases the biosynthesis of both NA and DA, the effects of oxygen depletion on the functional activities of NA neurons differ considerably from those of DA neurons: Only in the cerebral cortex and hippocampus are the NA neurons slightly sensitive to hypoxia, whereas the DA neurons are most sensitive in all brain regions.


Functional and biochemical aspects of catecholamine metabolism in brain under hypoxia
http://www.sciencedirect.com/scienc...serid=10&md5=133281ed874c51c5eca7f756a7005d3f


> Animals exposed to 6% oxygen showed a partial inhibition of the rate of tyrosine hydroxylation and a blockade of the conditioned avoidance response. The behavioral disruption was suggested to result, at least in part, from a dopaminergic disturbance, since the behavior was restored by the administration of DOPA or apomorphine but not by 5-hydroxytryptophan. Biochemical data showed a selective retardation in brain dopamine (DA) disappearance after synthesis inhibition. Methoxytyramine formation was markedly retarded. Analysis of this effect indicated that the decreased DA turnover was related to the release of transmitter rather than to an effect on catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO).
> In addition, there was evidence for a partial inhibition of MAO activity by hypoxia as well as a decreased activity of dopamine-β-hydroxylase. It was concluded that the disruption of behavior was related to decreased dopaminergic receptor activation and that decreased synthesis played at most a contributory role.


THE EFFECT OF HYPOXIA ON MONOAMINE SYNTHESIS, LEVELS AND METABOLISM IN RAT BRAIN
http://www3.interscience.wiley.com/journal/119673657/abstract


> Abstract-Rats were exposed to 5.6% oxygen environments for up to 2 h. The accumulation of brain DOPA and 5-hydroxytryptophan at 30 min after decarboxylase inhibition was used to estimate cerebral tryosine and tryptophan hydroxylase activity, respectively, in vivo. There was a continuing decrease in tryosine hydroxylase activity during the 2 h in whole brain as well as five brain regions. Tryptophan hydroxylase activity declined during the 1st h, but then increased towards control levels during the 2nd h. There was an increase in brain tryptophan during the 2nd h as well. In whole brain and the five brain regions, there was no significant change in the levels of noradrenaline, dopamine or 5-hydroxytrypamine. During a 1 h exposure to 5.6% oxygen, there was decreased accumulation of noradrenaline, dopamine and 5-hydroxytryptamine after MAO inhibition and decreased accumulation of homovanillic acid and 5-hydroxyindoleacetic acid after probenecid administration. The dercreased synthesis and metabolism of the monoamines is most likely attributable to insufficient brain tissue oxygen as a substrate for the two hydroxylase enzymes.


Brain Lactate Is an Obligatory Aerobic Energy Substrate for Functional Recovery After Hypoxia: Further In Vitro Validation
http://www3.interscience.wiley.com/journal/119147935/abstract


> This study used the rat hippocampal slice preparation and the monocarboxylate transporter inhibitor, α-cyano-4-hydroxycinnamate (4-CIN), to assess the obligatory role that lactate plays in fueling the recovery of synaptic function after hypoxia upon reoxygenation. At a concentration of 500 µM, 4-CIN blocked lactate-supported synaptic function in hippocampal slices under normoxic conditions in 15 min. The inhibitor had no effect on glucose-supported synaptic function. Of control hippocampal slices exposed to 10-min hypoxia, 77.8 ± 6.8% recovered synaptic function after 30-min reoxygenation. Of slices supplemented with 500 µM 4-CIN, only 15 ± 10.9% recovered synaptic function despite the large amount of lactate formed during the hypoxic period and the abundance of glucose present before, during, and after hypoxia. These results indicate that 4-CIN, when present during hypoxia and reoxygenation, blocks lactate transport from astrocytes, where the bulk of anaerobic lactate is formed, to neurons, where lactate is being utilized aerobically to support recovery of function after hypoxia. These results unequivocally validate that brain lactate is an obligatory aerobic energy substrate for posthypoxia recovery of function.


I ll add some more here tomorrow when I have time


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## karoloydi (Feb 18, 2010)

Edwin said:


> Your last post also gave me an idea. It's possible these disorders (SAD/ADD) get progressively worse in time due to cell death caused by inefficient/disrupted use of glucose for energy. I wouldn't be surprised our dopaminergic neurons are falling like flies if these disorders are left untreated.
> 
> Interestingly, since starting DHA supplementation, which has remedied at least part of my symptoms, I've noticed a short adjustment period with day-time fatigue, baring all the symptoms of low blood sugar. This is some indirect anecdotal evidence for the usefulness of supplementing omega-3 fatty acids for these disorders.


BRAIN GLUCOSE AND ALZHEIMER'S

Brain changes may foretell Alzheimer's - reduced glucose utilization in the brain's parietal region among people who inherited apolipoprotein E-IV gene - Brief Article
http://findarticles.com/p/articles/mi_m1200/is_n12_v147/ai_16795958/


> Small's team knew that PET scans of people with Alzheimer's disease reveal a decreased ability to utilize glucose, a deficit that starts initially in the parietal cortex (see photo). This brain region is associated with memory, language, and other functions impaired by the disease process.............The reduction in glucose metabolism suggests that the neurons in the parietal region either aren't working well or have died, points out Zaven S. Khachaturian, an Alzheimer's researcher at the National Institute on Aging in Bethesda, Md. For people without dementia, such slight changes may be the first step in a decline leading many years later to full-blown disease, he says.


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## karoloydi (Feb 18, 2010)

And from what I ve been reading if the problem is actually low oxygen in brain then increasing the glucose in an oxygen deprived brain would not be a good idea:

Effect of glucose on perinatal hypoxic-ischemic brain damage.
http://www.ncbi.nlm.nih.gov/pubmed/1420620


> Investigations suggest that *hyperglycemia superimposed on hypoxia-ischemia or cerebral ischemia accentuates brain damage in adult experimental animals and humans.*


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## Edwin (Jun 19, 2008)

Check this out:

http://www.biomedsearch.com/nih/Effects-CDP-choline-neurologic-deficits/3344538.html

http://vitae.ucv.ve/pdfs/VITAE_2518.pdf

There are some relations between brain glucose levels and choline, and EPA/DHA + Cho/Inositol supplementation might be synergistic for the treatment of ADHD (and what's good for ADHD, is often good for SAD).


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## karoloydi (Feb 18, 2010)

I suggest resveratrol. It can help in a number of ways:
I ll copy my post from mindamdmuscle:

It can increase cerebral blood flow according to this study. It says that the increase in blood flow didnt effect congitive performance. But it didnt mention anything about mood and anxiety. And thats also in healthy people. Maybe in people that have a problem with cerebral blood flow will enhance their cognitive performance:

Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation.
http://www.ncbi.nlm.nih.gov/pubmed/20357044


> BACKGROUND: The many putative beneficial effects of the polyphenol resveratrol include an ability to bolster endogenous antioxidant defenses, modulate nitric oxide synthesis, and promote vasodilation, which thereby improves blood flow. Resveratrol may therefore modulate aspects of brain function in humans. OBJECTIVE: The current study assessed the effects of oral resveratrol on cognitive performance and localized cerebral blood flow variables in healthy human adults. DESIGN: In this randomized, double-blind, placebo-controlled, crossover study, 22 healthy adults received placebo and 2 doses (250 and 500 mg) of trans-resveratrol in counterbalanced order on separate days. After a 45-min resting absorption period, the participants performed a selection of cognitive tasks that activate the frontal cortex for an additional 36 min. Cerebral blood flow and hemodynamics, as indexed by concentration changes in oxygenated and deoxygenated hemoglobin, were assessed in the frontal cortex throughout the posttreatment period with the use of near-infrared spectroscopy. The presence of resveratrol and its conjugates in plasma was confirmed by HPLC after the same doses in a separate cohort (n = 9). RESULTS: Resveratrol administration resulted in dose-dependent increases in cerebral blood flow during task performance, as indexed by total concentrations of hemoglobin. There was also an increase in deoxyhemoglobin after both doses of resveratrol, which suggested enhanced oxygen extraction, that became apparent toward the end of the 45-min absorption phase and was sustained throughout task performance. Cognitive function was not affected. Resveratrol metabolites were present in plasma throughout the cognitive task period. CONCLUSION: These results showed that single doses of orally administered resveratrol can modulate cerebral blood flow variables.


Also Resveratrol increases fetal hemoglobin in blood. Fetal hemoglobin has higher capacity to carry oxygen. So probably this also means that this could increase oxygen in brain. Other substances that can increase fetal hemoglobin are also mentioned int his study:

Fetal Hemoglobin Inducers from the Natural World: A Novel Approach for Identification of Drugs for the Treatment of {beta}-Thalassemia and Sickle-Cell Anemia.
http://www.ncbi.nlm....pubmed/18955291


> The objective of this review is to present examples of lead compounds identified from biological material (fungi, plant extracts and agro-industry material) and of possible interest in the field of a pharmacological approach to the therapy of beta-thalassemia using molecules able to stimulate production of fetal hemoglobin (HbF) in adults. Concerning the employment of HbF inducers as potential drugs for pharmacological treatment of beta-thalassemia, the following conclusions can be reached: (i) this therapeutic approach is reasonable, on the basis of the clinical parameters exhibited by hereditary persistence of fetal hemoglobin patients, (ii) clinical trials (even if still limited) employing HbF inducers were effective in ameliorating the symptoms of beta-thalassemia patients, (iii) good correlation of in vivo and in vitro results of HbF synthesis and gamma-globin mRNA accumulation indicates that in vitro testing might be predictive of in vivo responses and (iv) combined use of different inducers might be useful to maximize HbF, both in vitro and in vivo. In this review, we present three examples of HbF inducers from the natural world: (i) angelicin and linear psoralens, contained in plant extracts from Angelica arcangelica and Aegle marmelos, (ii) resveratrol, a polyphenol found in grapes and several plant extracts and (iii) rapamycin, isolated from Streptomyces hygroscopicus.


It can also protect from cell deth during inschemia:

Resveratrol exerts its neuroprotective effect by modulating mitochondrial dysfunctions and associated cell death during cerebral ischemia
http://www.sciencedirect.com/science?_ob=A...3891be22c98bc10



> Free radicals are known to cause secondary neuronal damage in cerebral ischemia/reperfusion (I/R). We investigated here the neuroprotective effect of resveratrol, a potent antioxidant present in grape seed, against cerebral I/R-induced mitochondrial dysfunctions in hippocampus. Transient rat middle cerebral artery occlusion (MCAO) model of brain ischemia was used to induce brain infarction. Resveratrol (10− 7 g/kg) was given twice intravenously: 15 min pre-occlusion and at the time of reperfusion (2 h post-occlusion). Resveratrol significantly restored ATP content and the activity of mitochondrial respiratory complexes in resveratrol treated group which were severely altered in MCAO group. Western blot analysis showed a marked decrease in cytochrome c release as a result of resveratrol treatment. Electrophoretic migration of hippocampal genomic DNA showed a marked decrease in DNA fragmentation after resveratrol treatment. Notably, expression of Hsp70 and metallothionein (MT) was significantly higher in MCAO group but their expression was more significant in resveratrol treated group. The status of mitochondrial glutathione (GSH), glucose 6-phosphate dehydrogenase (G6-PD) and serum lactate dehydrogenase (LDH) was restored by resveratrol treatment with a significant decrease in mitochondrial lipid peroxidation (LPO), protein carbonyl and intracellular H2O2 content. Resveratrol significantly improved neurological deficits assessed by different scoring methods. Also, the brain infarct volume and brain edema were significantly reduced. Histological analysis of CA1 hippocampal region revealed that resveratrol treatment diminished intercellular and pericellular edema and glial cell infiltration. The findings of this study highlight the ability of resveratrol in anatomical and functional preservation of ischemic neurovascular units and its relevance in the treatment of ischemic stroke.


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## Samba (Apr 25, 2010)

Can you dumb this down for me and tell me the most beneficial 3 or 4 things I should take?

I'm giving up on effexor. 

I know fish oil helps.

I'm really tempted to try Sam-e. 

I have GAD, SA, and depression.


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## ElRey (Apr 9, 2010)

Very interesting articles guys. Thanks. 

I have a weird comment/question. In regards to the oxygen issue in the brain, I've had a chronic problem for years with my left ear popping when stressed out (normally out in public, etc.). Sometimes it'll stay like that for hours, sometimes causing headaches, primarily above my right eye. Could that be related to the oxygen in the brain? I've also noticed that when smoking (which I do a lot sometimes) can make it even worse. I mentioned to the psychiatrist I saw months back and he had no clue what it meant.

Has anyone on here even experienced something like that? There's not much on the net about it, unfortunately. Any opinions would be appreciated and sorry if this strays from the OP, I could be totally off base on this.


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## karoloydi (Feb 18, 2010)

Guide 4 Dummies said:


> I just want to report the complete success I experienced.
> 
> Today I took Pentoxifylline + Memantine + Piracetam + Omega 3, and shortly after I felt like I was in the dark and someone turned on the lights! I feel stimulated without the jitters, and guess what? SAD completely non-existent.
> 
> ...


How does it compare to your pramipexole experience?


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## karoloydi (Feb 18, 2010)

Some studies on Pentoxifylline:

The effect of pentoxifylline ('Trental') on cerebral blood flow: A double-blind study
http://informahealthcare.com/doi/abs/10.1185/03007997609112002


> A double-blind, placebo controlled crossover study was carried out in 20 geriatric patients with cerebrovascular insufficiency to assess the effect of pentoxifylline on cerebral blood flow. Using 99m Tc cerebral scintigraphy and a gamma camera/computer system, the pattern of blood flow in 5 brain areas was monitored after a single intravenous infusion of 200 mg pentoxifylline (10 ml) and after 10 ml saline solution. *The results showed that, with the exception of one brain area, there was a statistically significant increase both in regional and hemispheric cerebral blood flow after pentoxifylline*. It is of particular interest that global hemispheric blood flow, which gives an indication of total blood supply to the brain, showed approximately the same percentage increase on both sides with pentoxifylline.


Measurement of cerebral blood flow following intravenous administration of pentoxifyline ('Trentral').
http://www.ncbi.nlm.nih.gov/pubmed/844329


> Using 99mTc cerebral scintigraphy and a gamma camera/computer system, the pattern of cerebral blood flow in 5 brain areas was monitored in 30 geriatric patients with cerebrovascular insufficiency. Readings were compared on a within-patient basis for the following treatments: initial control (I), intravenous administration of 10 ml physiological saline solution (II), and intravenous administration of 10 ml (200 mg) pentoxifylline (III). By comparsion with treatment I and II, pentoxifylline produced significant increases in cerebral blood flow. It is suggested that this increase in perfusion is possibly due to an improvement in the flow properties of blood.


Pentoxifylline improves learning and memory in glutamate-lesioned rats.
http://www.ncbi.nlm.nih.gov/pubmed/10973504


> The present work shows the effects of pentoxifylline (ptx), on learning and memory in rats with hippocampal lesions induced by glutamate (glu). Immediately after stereotaxic procedures and in the absence or presence of glu lesions, animals were treated with ptx (50, 100, or 200 mg/kg, IP) for 6 days. Twenty-four hours after the last injection, behavior and memory tests were performed, animals were sacrificed, and hippocampi dissected for cAMP determination or histopathological studies. Results from the T-maze task showed a less learning ability in the glu-lesioned group compared to other ones. Ptx alone or associated with glu significantly improved memory acquisition, but not memory consolidation compared to glu-lesioned rats. Except for the increased locomotor activity observed in the ptx100+glu-treated group compared to saline, no other difference was detected in the open-field test. A significant impairment in avoidance performance was observed in glu-lesioned group as compared to saline or to other groups in the short as well as in the late phase of memory. All groups showed an improved water-maze performance over time with similar performances on the final day of acquisition. The impairment in memory retention observed in glu-lesioned rats was reversed by the pretreatment with ptx200. Glu induced hippocampal lesion and reduced cAMP levels. Both effects were blocked by ptx, suggesting that its action may be the result of increased cAMP levels and/or inhibition of adenosine A1 receptors.


A controlled study on the effect of pentoxifylline and an ergot alkaloid derivative on regional cerebral blood flow in patients with chronic cerebrovascular disease.
http://www.ncbi.nlm.nih.gov/pubmed/3288016


> Regional cerebral blood flow (rCBF) in 90 patients with CBF decreased due to vascular diseases was studied by using the xenon 133 inhalation technique and a 32-detector setup. Whereas 30 patients received their standard basic therapy only and were regarded as controls, 30 others received 3 x 2 mg/day of an ergot alkaloid (co-dergocrine mesylate), and 30 others received 3 x 400 mg pentoxifylline (slow-release formulation)/day orally. Therapy was performed for eight weeks and CBF measured before start of treatment, after a four-week treatment period, and at the end of the study. CBF did not change significantly in the control group; both the pentoxifylline and the ergot alkaloid group presented with a significant increase in the CBF. This positive effect was significantly more pronounced in the pentoxifylline group and affected more ischemic than other brain tissues. In addition, symptoms like sleep disturbances, vertigo, and tinnitus improved significantly during the pentoxifylline observation period.


Protective effects of pentoxifylline on the brain following remote burn injury.
http://www.ncbi.nlm.nih.gov/pubmed/20573453

Pentoxifylline treatment improves neurological and neurochemical deficits in rats subjected to transient brain ischemia.
http://www.ncbi.nlm.nih.gov/pubmed/19161991


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## Selection10 (Oct 7, 2009)

Very interesting.


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## karoloydi (Feb 18, 2010)

About piracetam:

Cerebral blood flow effects of piracetam, pentifylline, and nicotinic acid in the baboon model compared with the known effect of acetazolamide.
http://www.ncbi.nlm.nih.gov/pubmed/8876930


> In normal aging humans there is a progressive decrease of oxygen and glucose consumption with a reduction of cerebral blood flow (CBF), which could be responsible for age-related changes in cognitive functions. A baboon model under anaesthesia using single photon emission computed tomography (SPECT) of the brain and the radiopharmaceutical hexamethylpropylene amine oxime (99mTc-HMPAO) has been developed and found to be sensitive to the effects of drugs that are known to increase CBF. In the present study, the effect of two haemorrheologically active drugs, viz a combination of pentifylline (CAS 1028-33-7) and nicotinic acid (CAS 59-67-6) vs. piracetam (CAS 7491-74-9) were compared with the known effect of acetazolamide (CAS 59-66-5) on CBF in the baboon model using the 99mTc-HMPAO split dose method. Acetazolamide (p < 0.05) and the combination of pentifylline and nicotinic acid (p < 0.01) increased the CBF when compared with the control baseline. The CBF was not significantly increased upon treatment with piracetam, pentifylline alone and nicotinic acid alone, when compared with the control values for total brain ratios (p > 0.05). However, an increased regional effect was observed for piracetam. These results indicate that the above haemorrheologically active drugs exhibit specific but different effects on cerebral blood flow with possible clinical implications.


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## karoloydi (Feb 18, 2010)

Guide 4 Dummies said:


> I just want to report the complete success I experienced.
> 
> Today I took Pentoxifylline + Memantine + Piracetam + Omega 3, and shortly after I felt like I was in the dark and someone turned on the lights! I feel stimulated without the jitters, and guess what? SAD completely non-existent.
> 
> ...


I remember you told me your blood pressure is higher than normal.
Look at this study:

Cerebral blood flow and brain function in hypertension.
http://www.ncbi.nlm.nih.gov/pubmed/7584916


> In mild hypertensive patients, regional cerebral blood flow, measured by positron emission tomography, was reduced in the frontal cortex and basal ganglia compared with normotensive patients. *In moderate to severe hypertensive patients, cerebral oxygen metabolism was diminished, although the patients were neurologically intact*. In elderly hypertensives, white matter vascular lesions on brain imaging were more frequent and cognitive function was impaired, compared with age-matched normotensives. *In nontreated spontaneously hypertensive rats (SHR), local cerebral blood flow was decreased in the cortex and thalamus, compared with normotensive rats (NTR). Spatial memory and learning in maze tests were more impaired in aged SHR than in old NTR or young SHR. This impairment was related to decreased cerebral glucose utilization in the medial septal nucleus, hippocampus, and other regions of the brain*. Reduced cerebral blood flow, increased media thickness of the cerebral arteries and impaired cognitive function in SHR were improved by long-term antihypertensive treatment. In humans as well as animals, long-standing hypertension per se leads to reductions in cerebral blood flow, metabolism, and cognitive function, each of which *possibly may be improved by controlling hypertension with long-term antihypertensive treatment.*


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## karoloydi (Feb 18, 2010)

This article is very interesting. It mentions some drugs that could be good to try. It also mentions Pentoxifylline:

Pharmacology of nootropics and metabolically active compounds in relation to their use in dementia.
http://www.ncbi.nlm.nih.gov/pubmed/2190256


> The development of effective drugs for the treatment of dementia is an important therapeutic target. Drugs which stop the progression of dementia have not been developed; however, nootropics and metabolically active compounds such as the vinca alkaloids and the ergot alkaloids as well as alkylxanthines are widely used to alleviate the symptoms. This review summarises animal studies investigating the mechanism of action of these compounds and highlights gaps in our knowledge of their pharmacology. Nootropics, such as *piracetam, facilitate learning and retrieval of information and protect the brain from physical and chemical intoxication*. Nootropics may produce these effects via an enhancement of acetylcholine or dopamine release; however, this postulate requires further evaluation. The pharmacology of vinca alkaloids is reviewed with particular reference to *vinpocetine. This compound attenuates cognitive deficits, reduces ischaemia-induced hippocampal cell loss and increases cerebral blood flow and glucose utilisation.* These effects may be induced by modulation of cyclic nucleotide levels and adenosine re-uptake inhibition. An extensively examined ergot alkaloid is *co-dergocrine; this compound increases both the oxygen tension and the electrical activity of the ischaemic cerebral cortex.* Alkylxanthines have a wide range of pharmacological activities, and in this review the pharmacology of pentoxifylline, propentofylline and denbufylline is contrasted with that of theophylline and caffeine. In particular, the pharmacology of propentofylline and the selective low Km cyclic AMP phosphodiesterase inhibitor denbufylline is summarised. Although more carefully controlled clinical trials in well defined patient collectives are required, present evidence suggests some therapeutic efficacy for nootropics and metabolically active compounds. Further studies to more closely evaluate their mechanism of action may lead to the development of more effective agents for the therapy of dementia.


I found those colllection of studies in Mind and Muscle about co-dergocrine:
http://www.mindandmuscle.net/forum/index.php?showtopic=34159&hl=co-dergocrine


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## crayzyMed (Nov 2, 2006)

Thank you for posting your experience Guide4dummies, looks like there really is something to this, also props to kariyoldi for putting this thread togheter, there's some really good information here!

I am thinking of a combo of Pentoxifylline + Memantine + Piracetam + Omega 3 + Resveratrol, will keep yall updated.


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## crayzyMed (Nov 2, 2006)

ElRey said:


> Very interesting articles guys. Thanks.
> 
> I have a weird comment/question. In regards to the oxygen issue in the brain, I've had a chronic problem for years with my left ear popping when stressed out (normally out in public, etc.). Sometimes it'll stay like that for hours, sometimes causing headaches, primarily above my right eye. Could that be related to the oxygen in the brain? I've also noticed that when smoking (which I do a lot sometimes) can make it even worse. I mentioned to the psychiatrist I saw months back and he had no clue what it meant.
> 
> Has anyone on here even experienced something like that? There's not much on the net about it, unfortunately. Any opinions would be appreciated and sorry if this strays from the OP, I could be totally off base on this.


Hmm, i wouldnt know i gues the best way to find out is by trying supplements that improve oxygen to the brain.


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## karoloydi (Feb 18, 2010)

crayzyMed said:


> Thank you for posting your experience Guide4dummies, looks like there really is something to this, also props to kariyoldi for putting this thread togheter, there's some really good information here!
> 
> I am thinking of a combo of Pentoxifylline + Memantine + Piracetam + Omega 3 + Resveratrol, will keep yall updated.


This is my ultimate combo that I ll be doing soon:

Pentoxifylline + Memantine + Piracetam + co-dergocrine (also maybe Lion's Mane + Picamilon) will be the ones that will form the basis of my regimen.
Then those will be the addons I am already taking:

Resveratrol (I think I ll increase to 1g/day)
Alpha Lipoic Acid
N Acetyl Cycteine
Omega 3,6,9
Liquorice
CoQ10
Condroitin Glucosamine MSM (thats not really for the brain)
A-Z Multivitamins
Acetyl L Carnitine
Dark Chocolate
Methyl B12
Methylfolate
D3
(I also wanna try Super Green Max Plus from Swanson that has various good stuff like royal jelly, wheat grass, ginkgo biloba, milk thistle, chlorella)


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## karoloydi (Feb 18, 2010)

Guide 4 Dummies said:


> Hydergine? It's alpha-adrenergic antagonist at alpha-1. alpha-1b is responsible for dopamine release. Please reconsider.


I ll do some more studying on this. I thought it just increases congitive performance. What really I liked was its effect on oxygen levels:


> Studies have shown that Hydergine helps to stabilize brain oxygen levels. (14) If brain oxygen levels are too low then Hydergine raises them, and if they're too high then Hydergine lowers them


Those are the full range of benefits I found in that mind and muscle thread:
http://www.mindandmuscle.net/forum/index.php?showtopic=34159
Increase blood supply to the brain. 
Increase oxygen delivered to the brain. 
Enhance metabolism of brain cells. 
Protect the brain from insufficient oxygen supply. 
Slow the deposit of the age pigment lipofuscin in the brain. 
Prevent free radical damage to brain cells. 
Increase intelligence, memory, learning and recall.

I also found this on the same thread:


> Studies have demonstrated that Hydergine actually increases cortical thickness in the brain through this process and that it also raises levels of the neurotransmitter dopamine. (13)


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## Ehsan (Mar 21, 2009)

Guide 4 Dummies said:


> alpha-1b is responsible for dopamine release.


could you please give some references?


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## crayzyMed (Nov 2, 2006)

5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants
Quote:
Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of alpha1b-adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an alpha1-adrenergic antagonist. However, morphine-induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the alpha1b-adrenergic receptor (alpha1b-AR KO) and in wild-type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine-evoked DA release was completely blocked in alpha1b-AR KO mice by SR46349B (1 mg/kg), a 5-HT2A antagonist. SR46349B also completely blocked, in alpha1b-AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and D-amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5-HT2A and alpha1b-adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, D-amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or D-amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5-HT2A receptors for the genetic deletion of alpha1b-adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.


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## karoloydi (Feb 18, 2010)

I edited the post. I ll copy this again cause you ll probably wont see it:


> Studies have demonstrated that Hydergine actually increases cortical thickness in the brain through this process and that it also raises levels of the neurotransmitter dopamine. (13)


I found the reference it comes from:

Behavioral and neurochemical effects of hydergine in rats
http://www.ncbi.nlm.nih.gov/pubmed/6118105


> Effects of various (20, 40 or 80 mg/kg; intragastric instillation) doses of Hydergine (dihydroergotoxine) were studied on the self-stimulation (SS) behavior (in young and old rats with electrodes implanted in the A10 area) and also on spontaneous motor activity (SMA) and stereotypy (ST) as well as on the concentrations of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and gamma-aminobutyric acid (GABA) in discrete brain areas, such as caudate nucleus (CN), pons-medulla (PM) and diencephalon-midbrain (DM) in adult rats. Following Hydergine administration, SS and SMA showed a dose-dependent increase with peak effects occurring between 80-120 min and then decreased. ST was not induced at any dose. DA and NE levels in the DM also showed a dose-dependent increase at 90 min and then sharply decreased up to 120 min after drug administration. NE in the PM and DA in the CN showed a similar pattern, but to a smaller degree. GABA in the DM and CN showed marked increases up to 120 min, while 5-HT in the PM and DM showed steady declines during the same period. Thus it appears that the behavioral stimulant effects of Hydergine may be correlated to increase in NE and DA levels, particularly in the DM.


But its not very clear. It says after 120 mins its decreasing. Is it decreasing to normal values, or below normal values? And 120 mins is not that long.


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## crayzyMed (Nov 2, 2006)

Yeah, actually i quite like hydergine, its close related to LSD and hoffman took it for a long time and got pretty old, problem is that it could cause fibrosis. (search pubmed for hydergine and fibrosis, its a 5HT2B agonist) altough the risk is very small i think.

Actually i doubt the 5HT1B antagonism is very significant since on bluelight many take it and i havent heared it blocks other drugs.


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## karoloydi (Feb 18, 2010)

crayzyMed said:


> Yeah, actually i quite like hydergine, its close related to LSD and hoffman took it for a long time and got pretty old, problem is that it could cause fibrosis. (search pubmed for hydergine and fibrosis, its a 5HT2B agonist) altough the risk is very small i think.
> 
> Actually i doubt the 5HT1B antagonism is very significant since on bluelight many take it and i havent heared it blocks other drugs.


And I think its gonna be a good safety net. We are walking into uncharted territory. We dont want to increase oxygen to dangerous levels
This is from the same thread:


> Oxygen is unique in that it is both a free radical generator and a free radical scavenger. At optimum concentrations, oxygen neutralizes more free radicals than it produces. Either too much or too little can upset the balance and generate the production of free radicals, which in turn can lead to aging.


So, with its ability to stabilise oxygen levels, I think hydergine could be good for this.


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## karoloydi (Feb 18, 2010)

Guide 4 Dummies said:


> I have Hydergine in my drawer, I'll take 1 pill and report back what happens.
> 
> EDIT: No noticeable effect, maybe it's working, maybe not.


Let me know how its working for you so that I ll know if I m gonna buy or not.


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## crayzyMed (Nov 2, 2006)

Seems like Pentoxifylline is a global PDE inhibitor, here's some interesting info:

Seems like they could work for shizophrenia:


> Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications.
> Maxwell CR, Kanes SJ, Abel T, Siegel SJ.
> 
> Stanley Center for Experimental Therapeutics in Psychiatry, Division of Neuropsychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
> ...


Also PDE4 inhibition should reverse the cognitive impairment induced by sleep deprivation:
http://news.bbc.co.uk/2/hi/health/8315818.stm

And should work as potent cognitive enhancers:


> Selective phosphodiesterase inhibitors: a promising target for cognition enhancement
> 
> Abstract
> Rationale
> ...


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## euphoria (Jan 21, 2009)

I think I heard something about hydergine also causing fibrosis...


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## karoloydi (Feb 18, 2010)

We ve got a big enough group here to do an experiment on this. If it works for the majority of us then theres light for us at the end of the tunnel.

After G4D, Crazy Med and Me will try first. If we see similar results as G4D then I am sure others will follow.


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## karoloydi (Feb 18, 2010)

EXERCISE AND LACTATE / GLUCOSE / OXYGEN

Heres some further information on what happens in the brain when theres decreased availability in glucose and oxygen.

High intensity exercise decreases global brain glucose uptake in humans
http://jp.physoc.org/content/568/1/323.abstract


> Physiological activation increases glucose uptake locally in the brain. However, it is not known how high intensity exercise affects regional and global brain glucose uptake. The effect of exercise intensity and exercise capacity on brain glucose uptake was directly measured using positron emission tomography (PET) and [18F]fluoro-deoxy-glucose ([18F]FDG). Fourteen healthy, right-handed men were studied after 35 min of bicycle exercise at exercise intensities corresponding to 30, 55 and 75% of on three separate days. [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning of the brain was conducted after completion of the exercise. Regional glucose metabolic rate (rGMR) decreased in all measured cortical regions as exercise intensity increased. The mean decrease between the highest and lowest exercise intensity was 32% globally in the brain (38.6 ± 4.6 versus 26.1 ± 5.0 μmol (100 g)−1 min−1, P < 0.001). Lactate availability during exercise tended to correlate negatively with the observed brain glucose uptake. In addition, the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex (37% versus 20%, P < 0.05 between 30% and 75% of ) was significantly more pronounced in subjects with higher exercise capacity. These results demonstrate that brain glucose uptake decreases with increase in exercise intensity. Therefore substrates other than glucose, most likely lactate, are utilized by the brain in order to compensate the increased energy needed to maintain neuronal activity during high intensity exercise. Moreover, it seems that exercise training could be related to adaptive metabolic changes locally in the frontal cortical regions.


Lactate fuels the human brain during exercise
http://www.fasebj.org/cgi/content/abstract/22/10/3443


> The human brain releases a small amount of lactate at rest, and even an increase in arterial blood lactate during anesthesia does not provoke a net cerebral lactate uptake. However, during cerebral activation associated with exercise involving a marked increase in plasma lactate, the brain takes up lactate in proportion to the arterial concentration. Cerebral lactate uptake, together with glucose uptake, is larger than the uptake accounted for by the concomitant O2 uptake, as reflected by the decrease in cerebral metabolic ratio (CMR) [the cerebral molar uptake ratio O2/(glucose+ lactate)] from a resting value of 6 to <2. The CMR also decreases when plasma lactate is not increased, as during prolonged exercise, cerebral activation associated with mental activity, or exposure to a stressful situation. The CMR decrease is prevented with combined β1- and β2-adrenergic receptor blockade but not with β1-adrenergic blockade alone. Also, CMR decreases in response to epinephrine, suggesting that a β2-adrenergic receptor mechanism enhances glucose and perhaps lactate transport across the blood-brain barrier. The pattern of CMR decrease under various forms of brain activation suggests that lactate may partially replace glucose as a substrate for oxidation. Thus, the notion of the human brain as an obligatory glucose consumer is not without exceptions.-Quistorff, B., Secher, N. H., and Van Lieshout, J. J. Lactate fuels the human brain during exercise.


*Theres an interesting mention about ammonia in this article. It says that when theres not enough glycogen the brain cant get rid of ammonia and its building up inside the brain. I ll look into this further. From what I remember ammonia is linked with ADHD and autism:*

Cerebral blood flow and metabolism during exercise: implications for fatigue. 
http://jap.physiology.org/cgi/content/abstract/104/1/306


> During exercise: the Kety-Schmidt-determined cerebral blood flow (CBF) does not change because the jugular vein is collapsed in the upright position. In contrast, when CBF is evaluated by 133Xe clearance, by flow in the internal carotid artery, or by flow velocity in basal cerebral arteries, a 25% increase is detected with a parallel increase in metabolism. During activation, an increase in cerebral O2 supply is required because there is no capillary recruitment within the brain and increased metabolism becomes dependent on an enhanced gradient for oxygen diffusion. During maximal whole body exercise, however, cerebral oxygenation decreases because of eventual arterial desaturation and marked hyperventilation-related hypocapnia of consequence for CBF. Reduced cerebral oxygenation affects recruitment of motor units, and supplemental O2 enhances cerebral oxygenation and work capacity without effects on muscle oxygenation. Also, the work of breathing and the increasing temperature of the brain during exercise are of importance for the development of so-called central fatigue. *During prolonged exercise, the perceived exertion is related to accumulation of ammonia in the brain, and data support the theory that glycogen depletion in astrocytes limits the ability of the brain to accelerate its metabolism during activation.* The release of interleukin-6 from the brain when exercise is prolonged may represent a signaling pathway in matching the metabolic response of the brain. Preliminary data suggest a coupling between the circulatory and metabolic perturbations in the brain during strenuous exercise and the ability of the brain to access slow-twitch muscle fiber populations.


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## karoloydi (Feb 18, 2010)

This is really interesting guys. Adrenaline increases both glucose and oxygen in brain. Noradrenaline increases just glucose:

Cerebral non-oxidative carbohydrate consumption in humans driven by adrenaline
http://jp.physoc.org/content/587/1/285.abstract


> During brain activation, the decrease in the ratio between cerebral oxygen and carbohydrate uptake (6 O2/(glucose + 1/2 lactate); the oxygen-carbohydrate index, OCI) is attenuated by the non-selective β-adrenergic receptor antagonist propranolol, whereas OCI remains unaffected by the β1-adrenergic receptor antagonist metroprolol. These observations suggest involvement of a β2-adrenergic mechanism in non-oxidative metabolism for the brain. Therefore, we evaluated the effect of adrenaline (0.08 μg kg−1 min−1I.V. for 15 min) and noradrenaline (0.5, 0.1 and 0.15 μg kg−1 min−1I.V. for 20 min) on the arterial to internal jugular venous concentration differences (a-v diff) of O2, glucose and lactate in healthy humans. Adrenaline (n = 10) increased the arterial concentrations of O2, glucose and lactate (P < 0.05) and also increased the a-v diff for glucose from 0.6 ± 0.1 to 0.8 ± 0.2 mM (mean ± S.D.; P < 0.05). The a-v diff for lactate shifted from a net cerebral release to an uptake and OCI was lowered from 5.1 ± 1.5 to 3.6 ± 0.4 (P < 0.05) indicating an 8-fold increase in the rate of non-oxidative carbohydrate uptake during adrenaline infusion (P < 0.01). Conversely, noradrenaline (n = 8) did not affect the OCI despite an increase in the a-v diff for glucose (P < 0.05). These results support that non-oxidative carbohydrate consumption for the brain is driven by a β2-adrenergic mechanism, giving neurons an abundant provision of energy when plasma adrenaline increases.


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## karoloydi (Feb 18, 2010)

This is really great info. I need to study more about the oxygen/carbohydrate index its mentioning in the study. This is also one of many studies that I ve read that lactate is increased in the brain during brain injury. Are we brain damaged? Specifically it says that under normal conditions the brain is not taking any lactate from the body. Its using the lactate that is being produced in the brain as a product of glycolysis. Meaning that after glucose has been metabolised in the brain lactate is kind of the waste product of the process. But when theirs a brain injury the brain is using the lactate from the body.
Also it showes that noradrenaline is a better candidate for increasing glucose than adrenaline. Adrenaline is increasing both lactate and glucose. Noradrenaline is increasing only glucose, but this happens in small doses.

Non-oxidative cerebral carbohydrate metabolism
http://jp.physoc.org/content/587/1/9.full


> Kety and Schmidt's application of the Fick Principle in the 1940s has served as the technical basis for the human cerebral metabolic studies still in use today. In this technique, arterial and jugular venous blood samples are collected, analysed for oxygen, glucose and lactate, and an arterial-jugular venous difference (AVD) is calculated. The cerebral metabolic rate is then calculated as the product of the AVD and the simultaneous measurement of cerebral blood flow. To further understand the relationship between the cerebral metabolic components, an oxygen-carbohydrate index (OCI), calculated by , or a metabolic ratio (OGI), calculated by , is used to determine how much fuel substrate is oxidized, where a value of 6 represents the complete oxidation of glucose.
> 
> Glucose is considered to be the preferred cerebral oxidative fuel source under normal resting conditions, with 90% of brain glucose used oxidatively. The remaining 10% of glucose goes to non-oxidative uses, such as glycogen formation and other metabolic processes (Siesjö, 1978). On the other hand, in normal resting volunteers, the arterial jugular venous difference for lactate (AVDlac) is negative, indicating that the brain is producing and releasing lactate primarily through glycolysis. *However, strenuous exercise or traumatic brain injury studies reveal that the brain has a positive AVDlac, and is therefore taking up lactate* (Ide et al. 1999; Glenn et al. 2003; Soustiel & Sviri, 2007; Dalsgaard, 2006). Furthermore, the OCI/OGI can be influenced by brain activation or brain insult, with values dropping significantly due to a greater uptake of glucose and lactate relative to oxygen.
> 
> ...


EDIT: I found one study that shows that norepipehrine can reduce cerebral oxygenation:

Is cerebral oxygenation negatively affected by infusion of norepinephrine in healthy subjects?
http://bja.oxfordjournals.org/cgi/content/abstract/102/6/800


> Background: Vasopressor agents are commonly used to increase mean arterial pressure (MAP) in order to secure a pressure gradient to perfuse vital organs. The influence of norepinephrine on cerebral oxygenation is not clear. The aim of this study was to evaluate the impact of the infusion of norepinephrine on cerebral oxygenation in healthy subjects.
> 
> Methods: Three doses of norepinephrine (0.05, 0.1, and 0.15 µg kg-1 min-1 for 20 min each) were infused in nine healthy subjects [six males; 26 (6) yr, mean (SD)]. MAP, cerebral oxygenation characterized by frontal lobe oxygenation (ScO2) and internal jugular venous oxygen saturation (SjvO2), middle cerebral artery mean flow velocity (MCA Vmean), cardiac output (CO), and arterial partial pressure for carbon dioxide (PaCO2) were evaluated.
> 
> ...


But if we see the two studies combined maybe theres an optimal dose that it increases glucose while not affecting oxygen. Cause the first one says that at low doses it increases glucose but not lactate. That means to me that when you administer higher doses you decrease oxygen and this is why theres an increase in lactate.
Can someone interpret the figures from the last study? it says that norepinephrine needs to be at 0.1 µg kg-1 min-1 or lower. So for an 80kg man like me, is this 8 mg administered as an injection? How much would that be for example if you took something like wellbutrin or strattera? Its a bit confusing to me.


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## karoloydi (Feb 18, 2010)

OXYGEN GLUCOSE AND GABA

It looks like low oxygen affects GABA as well:

Alterations in cortical GABA(B) receptors in neonatal rats exposed to hypoxic stress: role of glucose, oxygen, and epinephrine resuscitation
http://www.ncbi.nlm.nih.gov/pubmed/20473556


> Hypoxia in neonates can cause permanent brain damage by gene and receptor level alterations mediated through changes in neurotransmitters. The present study evaluated GABA(B) receptor alterations, gene expression changes in glutamate decarboxylase and hypoxia-inducible factor 1A in the cerebral cortex of hypoxic neonatal rats and the resuscitation groups with glucose, oxygen, and epinephrine. Under hypoxic stress, a significant decrease in total GABA and GABA(B) receptors, GABA(B) and GAD gene expression was observed in the cerebral cortex, which accounts for the respiratory inhibition. Hypoxia-inducible factor 1A was upregulated under hypoxia to maintain body homeostasis. Hypoxic rats supplemented with glucose alone and with oxygen showed a reversal of the receptor alterations and changes in GAD and HIF-1A to near control. Being a source of immediate energy, glucose can reduce the ATP-depletion-induced changes in GABA and oxygenation, which helps in encountering hypoxia. Resuscitation with oxygen alone and epinephrine was less effective in reversing the receptor alterations. Thus, our study suggests that reduction in the GABA(B) receptors functional regulation during hypoxia plays an important role in cortical damage. Resuscitation with glucose alone and glucose and oxygen to hypoxic neonatal rats helps in protecting the brain from severe hypoxic damage.


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## karoloydi (Feb 18, 2010)

More on oxygen glucose and dopamine:

Dopamine D1 and D2 receptor functional down regulation in the cerebellum of hypoxic neonatal rats: neuroprotective role of glucose and oxygen, epinephrine resuscitation.
http://www.ncbi.nlm.nih.gov/pubmed/19720148


> Brain damage due to an episode of hypoxia remains a major problem in infants causing deficit in motor and sensory function. Molecular processes regulating the dopamine receptors play a very important role in motor and cognitive functions. Disturbances in the development of the dopaminergic system lead to dyskinesia, dystonia, tics and abnormal eye movements. The present study is to understand the hypoxic damage to the dopamine content and dopamine D(1), dopamine D(2) receptors in cerebellum and the neuroprotective effect of glucose supplementation prior to the current sequence of resuscitation-oxygen and epinephrine supplementation in neonatal rats. *Dopamine content in the cerebellum showed a significant decrease in hypoxic neonatal rats when compared to control. Dopamine D(1) and dopamine D(2) receptors showed a decrease in B(max) during hypoxia.* The cerebellar dopamine, dopamine D(1) and dopamine D(2) receptors showed significant decrease on supplementation of 100% oxygen alone to hypoxic rats when compared to control rats. Dopamine D(1) and dopamine D(2) receptors mRNA showed significant decrease during epinephrine supplementation prior to resuscitation. *These dopaminergic receptor alterations were reversed to near control by glucose supplementation.Thus our results suggest that glucose acts as a neuroprotective agent in dopaminergic receptors function*. This has immense clinical significance to correct the resuscitation sequence in neonatal care. Copyright 2009 Elsevier Ltd. All rights reserved.


[Dopamine D4 receptor hypoxia sensitivity and child psychiatric disorders.]
http://www.ncbi.nlm.nih.gov/pubmed/20305304


> Attention-deficit hyperactivity disorder (ADHD) is one of the most frequent child psychiatric problems with a complex genetic and environmental background. According to the prevailing view, main factors of the disorder are prefrontal dopamine deficiency and incomplete central dopaminergic functioning. Twin studies suggest substantial heritability in the background of the disease, and the studied candidate genes involve components of the dopamine system. Moreover, various noxious pre- and perinatal environmental impacts have been implicated in the pathogenesis of ADHD. *Here we review experimental results from epidemiological, tissue and animal studies that assigned a causal role to fetal hypoxia in the development of ADHD and pointed out that the dopaminergic neurotransmission is sensitive to hypoxia*. Allelic variants of the D4 dopamine receptor (DRD4) are well characterized risk factors of ADHD. Recently we have reported that hypoxia enhanced the promoter activity of DRD4 gene several fold. *These observations suggest that the effect of hypoxia on the dopaminergic neurotransmission might be an important factor in the pathomechanism of ADHD.*


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## karoloydi (Feb 18, 2010)

OXYGEN GLUCOSE AND OXYTOCIN

Oxytocin is neuroprotective against oxygen-glucose deprivation and reoxygenation in immature hippocampal cultures
http://www.ncbi.nlm.nih.gov/pubmed/20399835


> Oxytocin triggers an excitatory-to-inhibitory switch in GABA (gamma-aminobutyric acid) actions in immature neurons and this was found to increase their resistance to anoxic episodes. In this study we examined the neuroprotective effect of oxytocin on immature hippocampal cultures subjected to oxygen-glucose deprivation (OGD) both immediately after the insult, as well as after 6h of reoxygenation. We measured metabolic activity fluorometrically using resazurin and found that cellular viability was increased in the oxytocin treated group both immediately after OGD, as well as after 6 h of reoxygenation. While the oxytocin receptor antagonist atosiban blocked the effect of oxytocin, the Na+-K+-2Cl(-) cotransporter (NKCC1) blocker bumetanide protected neurons after reoxygenation. The effects of oxytocin are dose-related. Our results suggest that oxytocin exerts a prolonged neuroprotective action on fetal neurons. Perinatal pharmacologic manipulation of oxytocin receptors may have detrimental effects by increasing susceptibility of the fetal brain to hypoxic-ischemic insults. 2010 Elsevier Ireland Ltd. All rights reserved.


Anyone knows if women have lower chances of getting autism/ADHD/autism than men? And if oxytocin is high in women of all ages (even children?)

EDIT: I found some more info. It looks like I am right:

http://www.sciencedaily.com/releases/2007/07/070724113757.htm


> Men and women are equally as likely to acquire a spontaneous mutation that can cause autism, *but autism is three times more likely in men*,


Have a look at this one. It says that the sutistic brain has problem empathising. Empathy is closely related with oxytocin:

Sex Differences in the Brain: Implications for Explaining Autism
http://www.mmjb.info/cgi/content/abstract/310/5749/819


> Empathizing is the capacity to predict and to respond to the behavior of agents (usually people) by inferring their mental states and responding to these with an appropriate emotion. Systemizing is the capacity to predict and to respond to the behavior of nonagentive deterministic systems by analyzing input-operation-output relations and inferring the rules that govern such systems. At a population level, females are stronger empathizers and males are stronger systemizers. *The "extreme male brain" theory posits that autism represents an extreme of the male pattern (impaired empathizing and enhanced systemizing)*. Here we suggest that specific aspects of autistic neuroanatomy may also be extremes of typical male neuroanatomy.


Plasma oxytocin levels in autistic children
http://www.biologicalpsychiatryjournal.com/article/S0006-3223(97)00439-3/abstract


> Despite individual variability and overlapping group distributions, the autistic group mad significantly lower plasma OT levels than the normal group. OT increased with age in the normal but not the autistic children. Elevated OT was associated with higher scores on social and developmental measures for the normal children, but was associated with lower scores for the autistic children. These relationships were strongest in a subset of autistic children identified as aloof.


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## karoloydi (Feb 18, 2010)

KETON BODIES

I have done some more research. Keton bodies in an alternative source that our brains can use that looks like its equally good (or maybe even better) than glucose.

Chronic ketosis and cerebral metabolism
http://www3.interscience.wiley.com/journal...=1&SRETRY=0


> The effects of chronic ketosis on cerebral metabolism were determined in adult rats maintained on a high -fat diet for approximately three weeks and compared to a control group of animals. The fat-fed rats had statistically significantly lower blood glucose concentrations and higher blood -hydroxybutyrate and acetoacetate concentrations; higher brain concentrations of bound glucose, glucose 6-phosphate, pyruvate, lactate, -hydroxybutyrate, citrate, -ketoglutarate, alanine, and adenosine triphosphate (ATP); lower brain concentration of fructose 1,6-diphosphate, aspartate, adenosine diphosphate (ADP), creatine, cyclic nucleotides, succinyl coenzyme A (CoA), acid-insoluble CoA, and total CoA; and similar brain concentrations of glucose, malate, calculated oxaloacetate, glutamate, glutamine, adenosine monophosphate, phosphocreatine, reduced CoA, acetyl CoA, sodium, potassium, chloride, and water content. *The metabolite data in the chronically ketotic rats demonstrate an increase in the cerebral energy reserve and energy charge.* These data also suggest negative modification of the enzymes phosphofructokinase, pyruvic dehydrogenase, and -ketoglutaric dehydrogenase; positive modification of glycogen synthase; and possible augmentation of the hexose transport system. There was no demonstrable difference in brain pH, water content, or electrolytes in the two groups of animals. We speculate that the increased brain ATP/ADP ratio is central to most, if not all, the observed metabolic perturbations and may account for the increased neuronal stability that accompanies chronic ketosis.


This one says it doesnt change from keto to non keto, but protein is really important:

Effects of unbalanced diets on cerebral glucose metabolism in the adult rat
http://www.neurology.org/cgi/content/abstract/45/12/2261


> From the Departments of Neurology (Drs. Al-Mudallal and Harik) and Neurological Surgery (Dr. Lust), Case Western Reserve University School of Medicine, Cleveland, OH; and the Neurology Service (Dr. Levin), VA Medical Center, and Department of Neurosciences, New Jersey School of Medicine and Dentistry, Newark, NJ.
> Supported in part by USPHS grants HL 35617 and AM 30066 and by the Research Service of the Department of Veterans Administration.
> Received December 6, 1994. Accepted in final form March 28, 1995.
> Address correspondence and reprint requests to Dr. Sami I. Harik, Department of Neurology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 500, Little Rock, AR 72205.
> ...


Diet-induced ketosis increases capillary density without altered blood flow in rat brain
http://ajpendo.physiology.org/cgi/content/...act/292/6/E1607


> It is recognized that ketone bodies, such as R--hydroxybutyrate (-HB) and acetoacetate, are energy sources for the brain. As with glucose metabolism, monocarboxylate uptake by the brain is dependent on the function and regulation of its own transporter system. We concurrently investigated ketone body influx, blood flow, and regulation of monocarboxylate transporter (MCT-1) and glucose transporter (GLUT-1) in diet-induced ketotic (KG) rat brain. Regional blood-to-brain -HB influx (µmol·g-1·min-1) increased 40-fold with ketosis (4.8 ± 1.8 plasma-HB; mM) in all regions compared with the nonketotic groups (standard and no-fat diets); there were no changes in regional blood flow. Immunohistochemical staining revealed that GLUT-1 density (number/mm2) in the cortex was significantly elevated (40%) in the ketotic group compared with the standard and no-fat diet groups. MCT-1 was also markedly (3-fold) upregulated in the ketotic group compared with the standard diet group. In the standard diet group, 40% of the brain capillaries stained positive for MCT-1; this amount doubled with the ketotic diet. Western blot analysis of isolated microvessels from ketotic rat brain showed an eightfold increase in GLUT-1 and a threefold increase in MCT-1 compared with the standard diet group. These data suggest that diet-induced ketosis results in increased vascular density at the blood-brain barrier without changes in blood flow. *The increase in extraction fraction and capillary density with increased plasma ketone bodies indicates a significant flux of substrates available for brain energy metabolism.*


*This is really interesting too:*
Ketoacids? Good medicine?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194504/


> D-beta-hydroxybutyrate, the principal "ketone" body in starving man, displaces glucose as the predominating fuel for brain, decreasing the need for glucose synthesis in liver (and kidney) and accordingly spares its precursor, muscle-derived amino acids. Thus normal 70 kg. man survives 2-3 months of starvation instead of several weeks, and obese man many months to over a year. Without this metabolic adaptation, H. sapiens could not have evolved such a large brain. *Recent studies have shown that D-beta-hydroxybutyrate, the principal "ketone", is not just a fuel, but a "superfuel" more efficiently producing ATP energy than glucose or fatty acid. In a perfused rat heart preparation, it increased contractility and decreased oxygen consumption. It has also protected neuronal cells in tissue culture against exposure to toxins associated with Alzheimer's or Parkinson's.* In a rodent model it decreased the death of lung cells induced by hemorrhagic shock. Also, mice exposed to hypoxia survived longer. These and other data suggest a potential use of beta-hydroxybutyrate in a number of medical and non-medical conditions where oxygen supply or substrate utilization may be limited. Efforts are underway to prepare esters of beta-hydroxybutyrate which can be taken orally or parenterally to study its potential therapeutic applications.


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## karoloydi (Feb 18, 2010)

KETON BODIES (continued)

Ketone Bodies, Potential Therapeutic Uses
http://www.informaworld.com/smpp/content~d...tent=a713803796


> Ketosis, meaning elevation of D- β-hydroxybutyrate ( R -3-hydroxybutyrate) and acetoacetate, has been central to starving man's survival by providing nonglucose substrate to his evolutionarily hypertrophied brain, sparing muscle from destruction for glucose synthesis. Surprisingly, D- β-hydroxybutyrate (abbreviated " βOHB") may also provide a more efficient source of energy for brain per unit oxygen, supported by the same phenomenon noted in the isolated working perfused rat heart and in sperm. It has also been shown to decrease cell death in two human neuronal cultures, one a model of Alzheimer's and the other of Parkinson's disease. These observations raise the possibility that a number of neurologic disorders, genetic and acquired, might benefit by ketosis. Other beneficial effects from βOHB include an increased energy of ATP hydrolysis ( ΔG') and its linked ionic gradients. This may be significant in drug-resistant epilepsy and in injury and anoxic states. The ability of βOHB to oxidize co-enzyme Q and reduce NADP + may also be important in decreasing free radical damage. Clinical maneuvers for increasing blood levels of βOHB to 2-5 mmol may require synthetic esters or polymers of βOHB taken orally, probably 100 to 150 g or more daily. This necessitates advances in food-science technology to provide at least enough orally acceptable synthetic material for animal and possibly subsequent clinical testing. The other major need is to bring the technology for the analysis of multiple metabolic "phenotypes" up to the level of sophistication of the instrumentation used, for example, in gene science or in structural biology. This technical strategy will be critical to the characterization of polygenic disorders by enhancing the knowledge gained from gene analysis and from the subsequent steps and modifications of the protein products themselves.


This is good too:
Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet
http://www3.interscience.wiley.com/journal...501151/abstract


> *Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1DS, OMIM 606777) is caused by impaired glucose transport into brain mediated by GLUT1*, the glucose transporter at the blood-brain barrier. The condition is diagnosed by hypoglycorrhachia, impaired glucose uptake into erythrocytes, and heterozygous mutations in the SLC2A1 gene (OMIM 138140, gene map locus 1p35-31.3). Patients present with early-onset epilepsy, developmental delay, and a complex movement disorder. The phenotype is highly variable and several atypical variants have been described. *The ketogenic diet (KD) provides ketones as an alternative fuel to the brain*. Calculation, administration, supplements, and adverse effects of the KD in GLUT1DS do not differ from patients treated for intractable childhood epilepsy. In GLUT1DS, the KD should be introduced early to meet the energy demands of the developing brain and should be maintained into puberty. Seizures are effectively controlled, but the effects on neurodevelopment and on the movement disorder are less impressive. The KD remains the treatment of choice for GLUT1DS, but recent insights into anticonvulsive diet mechanisms, animal models for GLUT1DS, and the development of alternative KDs provide new opportunities to improve the treatment of this condition.


Diet-induced ketosis improves cognitive performance in aged rats.
http://www.ncbi.nlm.nih.gov/pubmed/20204773


> Aging is associated with increased susceptibility to hypoxic/ischemic insult and declines in behavioral function which may be due to attenuated adaptive/defense responses. We investigated if diet-induced ketosis would improve behavioral performance in the aged rats. Fischer 344 rats (3- and 22-month-old) were fed standard (STD) or ketogenic (KG) diet for 3 weeks and then exposed to hypobaric hypoxia. Cognitive function was measured using the T-maze and object recognition tests. Motor function was measured using the inclined-screen test. Results showed that KG diet significantly increased blood ketone levels in both young and old rats. In the aged rats, the KG diet improved cognitive performance under normoxic and hypoxic conditions; while motor performance remained unchanged. Capillary density and HIF-1alpha levels were elevated in the aged ketotic group independent of hypoxic challenge. These data suggest that diet-induced ketosis may be beneficial in the treatment of neurodegenerative conditions.


Ketogenic diet protects dopaminergic neurons against 6-OHDA neurotoxicity via up-regulating glutathione in a rat model of Parkinson's disease.
http://www.ncbi.nlm.nih.gov/pubmed/19559687


> The high-fat ketogenic diet (KD) leads to an increase of blood ketone bodies (KB) level and has been used to treat refractory childhood seizures for over 80 years. Recent reports show that KD, KB and their components (d-beta-hydroxybutyrate, acetoacetate and acetone) have neuroprotective for acute and chronic neurological disorders. In our present work, we examined whether KD protected dopaminergic neurons of substantia ***** (SN) against 6-hydroxydopamine (6-OHDA) neurotoxicity in a rat model of Parkinson's disease (PD) using Nissl staining and tyrosine hydroxylase (TH) immunohistochemistry. At the same time we measured dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum. To elucidate the mechanism, we also measured the level of glutathione (GSH) of striatum. Our data showed that Nissl and TH-positive neurons increased in rats fed with KD compared to rats with normal diet (ND) after intrastriatal 6-OHDA injection, so did DA and its metabolite DOPAC. While HVA had not changed significantly. The change of GSH was significantly similar to DA. We concluded that KD had neuroprotective against 6-OHDA neurotoxicity and in this period GSH played an important role.


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## karoloydi (Feb 18, 2010)

Keto diet also increases GABA

Ketogenic diet, brain glutamate metabolism and seizure control.
http://www.ncbi.nlm.nih.gov/pubmed/14769486?dopt=Abstract


> We do not know the mode of action of the ketogenic diet in controlling epilepsy. One possibility is that the diet alters brain handling of glutamate, the major excitatory neurotransmitter and a probable factor in evoking and perpetuating a convulsion. We have found that brain metabolism of ketone bodies can furnish as much as 30% of glutamate and glutamine carbon. *Ketone body metabolism also provides acetyl-CoA to the citrate synthetase reaction, in the process consuming oxaloacetate and thereby diminishing the transamination of glutamate to aspartate, a pathway in which oxaloacetate is a reactant. Relatively more glutamate then is available to the glutamate decarboxylase reaction, which increases brain [GABA]. Ketosis also increases brain [GABA] by increasing brain metabolism of acetate, which glia convert to glutamine. GABA-ergic neurons readily take up the latter amino acid and use it as a precursor to GABA.* Ketosis also may be associated with altered amino acid transport at the blood-brain barrier. Specifically, ketosis may favor the release from brain of glutamine, which transporters at the blood-brain barrier exchange for blood leucine. Since brain glutamine is formed in astrocytes from glutamate, the overall effect will be to favor the release of glutamate from the nervous system.


Also this:
Low-carb diets, fasting and euphoria: Is there a link between ketosis and gamma-hydroxybutyrate (GHB)?
http://www.ncbi.nlm.nih.gov/pubmed/17011713


> Anecdotal evidence links the initial phase of fasting or a low-carbohydrate diet with feelings of well-being and mild euphoria. These feelings have often been attributed to ketosis, the production of ketone bodies which can replace glucose as an energy source for the brain. One of these ketone bodies, beta-hydroxybutyrate (BHB), is an isomer of the notorious drug of abuse, GHB (gamma-hydroxybutyrate). GHB is also of interest in relation to its potential as a treatment for alcohol and opiate dependence and narcolepsy-associated cataplexy. Here I hypothesize that, the mild euphoria often noted with fasting or low-carbohydrate diets may be due to shared actions of BHB and GHB on the brain. Specifically, I propose that BHB, like GHB, induces mild euphoria by being a weak partial agonist for GABA(B) receptors. I outline several approaches that would test the hypothesis, including receptor binding studies in cultured cells, perception studies in trained rodents, and psychometric testing and functional magnetic resonance imaging in humans. These and other studies investigating whether BHB and GHB share common effects on brain chemistry and mood are timely and warranted, especially when considering their structural similarities and the popularity of ketogenic diets and GHB as a drug of abuse.


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## karoloydi (Feb 18, 2010)

NOW THE EXCITING PART!!!!!!!!!!!!!!!!!!!

I found a new drug that was developed last year that can increase keton bodies in our body (and brain) without having to go on a keto diet!

http://www.investegate.co.uk/article.aspx?...0302130000NM826


> *Axona targets the metabolic defects of
> glucose utilization in the brain by providing an alternative energy source.
> Axona is digested and metabolized by the liver to form ketone bodies,
> naturally occurring compounds produced by the body at low levels. These
> ...


The chemical name for this is Caprylidene. It came out about a year ago.
Theres not too much info on wikipedia:
http://en.wikipedia.org/wiki/Caprylidene

This is the official website:
http://www.about-axona.com/

If anyone can fond an online pharmacy that sells this let me know. (PM me if you re not allowed to post links to pharmacies)

On this forum I also found that Medium Chain Triglycerides (a supplement thats easiy to get hold of) are similar to Axona.
http://thealzheimerspouse.com/vanillaforum...scussionID=1593


> Mawzy, use MCT oil, it's better for you than coconut oil, and it's also closer in composition to Axona


According to people in this forum 20g of MCT oil (about 2 table spoons) is equivalent to the 40g dose of Axona

Also Omega Oils have similar capacity to increase keton bodies:

Omega-3 fatty acids, energy substrates, and brain function during aging
http://www.plefa.com/article/S0952-3278(06)00090-1/abstract


> he maintenance of optimal cognitive function is a central feature of healthy aging. Impairment in brain glucose uptake is common in aging associated cognitive deterioration, but little is known of how this problem arises or whether it can be corrected or bypassed. Several aspects of the challenge to providing the brain with an adequate supply of fuel during aging seem to relate to omega-3 fatty acids. For instance, low intake of omega-3 fatty acids, especially docosahexaenoic acid (DHA), is becoming increasingly associated with several forms of cognitive decline in the elderly, particularly Alzheimer's disease. *Brain DHA level seems to be an important regulator of brain glucose uptake, possibly by affecting the activity of some but not all the glucose transporters.* DHA synthesis from either α-linolenic acid (ALA) or eicosapentaenoic acid (EPA) is very low in humans begging the question of whether these DHA precursors are likely to be helpful in maintaining cognition during aging. We speculate that ALA and EPA may well have useful supporting roles in maintaining brain function during aging but not by their conversion to DHA. ALA is an efficient ketogenic fatty acid, while EPA promotes fatty acid oxidation. *By helping to produce ketone bodies, the effects of ALA and EPA could well be useful in strategies intended to use ketones to bypass problems of impaired glucose access to the brain during aging. Hence, it may be time to consider whether the main omega-3 fatty acids have distinct but complementary roles in brain function.*


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## Thorsten (Apr 6, 2010)

I was actually looking myself at this diet yesterday...

I'm really interested in the fact that it increases levels of BHB (similar to GHB) and is produced by the body in times of fasting. I've come across a couple of members over at Imminst who fast twice a week (also following a certain diet) and they say they haven't felt better in years. I don't think I'm there yet because I'm still researching this stuff but it would be interesting to try out.

I've just purchased a collection of books on brain health.

I think the Ketogenic diet sounds great in theory but (for me anyhow) it seems to contradict the fact that I display all of the symptons of Histadelia. It seems to be a common things in males especially.

Histadelia states that I must follow a low protein/complex carb/high vegetable diet (not including things like brocolli which is high in folic acid)...yet the thing is when I am on a high protein diet mixed with fruits I have never felt better in years (although this contradicts in theory because it would also raise histamine - maybe it's an illusion me?)..The only thing is when summer time comes I have hayfever symptons, depression and an intolerance of the hot weather...just a few of the lovely symptons I have to look forward to each summer (classic sides of high histamine according to histadelia theory)...

I haven't tried the histadelia diet yet though. It does say I have to take it with SAM-e and maybe a couple of other supps.

I think I'm going to try both these diets after I've done some reading on both.


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## Inshallah (May 11, 2011)

GREAT thread. This would show once gain that downers are certainly not the solution and a mere escape from reality. I'm starting to rethink the stimulant-idea perpetuated by many here


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