The "selfish brain" hypothesis for metabolic abnormalities in bipolar disorder and schizophrenia

Mansur, Rodrigo B.; Brietzke, Elisa

doi:10.1590/s2237-60892012000300003

Cited by 12 publications

(12 citation statements)

References 98 publications

(112 reference statements)

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“…It affects at least 1% of the population and leads to suicide in 15% of cases 1 . BD patients exhibit a higher prevalence of obesity, cardiovascular disease, and diabetes than the general population 2 , 3 . Many studies have shown that the pathophysiology of BD involves altered energy metabolism 4 – 8 .…”

Section: Introductionmentioning

confidence: 98%

Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae

Salsaa

Pereira

Liu

et al. 2020

Sci Rep

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the widely used mood stabilizer valproate (VpA) causes perturbation of energy metabolism, which is implicated in both the therapeutic mechanism of action of the drug as well as drug toxicity. to gain insight into these mechanisms, we determined the effects of VPA on energy metabolism in yeast. VpA treatment increased levels of glycolytic intermediates, increased expression of glycolysis genes, and increased ethanol production. increased glycolysis was likely a response to perturbation of mitochondrial function, as reflected in decreased membrane potential and oxygen consumption. interestingly, yeast, mouse liver, and isolated bovine cytochrome c oxidase were directly inhibited by the drug, while activities of other oxidative phosphorylation complexes (III and V) were not affected. These findings have implications for mechanisms of therapeutic action and toxicity. Bipolar disorder (BD) is a severe psychiatric illness characterized by shifts in mood, ranging from mania to depression. It affects at least 1% of the population and leads to suicide in 15% of cases 1. BD patients exhibit a higher prevalence of obesity, cardiovascular disease, and diabetes than the general population 2,3. Many studies have shown that the pathophysiology of BD involves altered energy metabolism 4-8. While most of the metabolic markers measured indicate mitochondrial dysfunction in BD 9-12 , some studies have suggested the presence of increased mitochondrial activity in the manic phase of BD 13 , including increased energy generation 14 , basal metabolic rate 15 , uric acid 16 , and calcium ions 17. Valproate (VPA) is one of several mood stabilizers approved by the FDA for the treatment of BD 18,19 , epilepsy 20,21 , and migraine 22. The mechanism of action of VPA is not understood 23. VPA is effective in only 40-60% of cases and can cause serious side effects, including hepatotoxicity and teratogenicity 24. Hepatotoxicity can be life-threatening 25,26 and may occur even at therapeutic doses 27. Although rare, lethal hepatotoxicity associated with VPA has been described in both children 28 and adults 29. The prominent feature of this type of hepatotoxicity is microvesicular steatosis 30 , consistent with mitochondrial dysfunction 31. In agreement with this, patients with congenital defects in mitochondrial metabolism are at a higher risk for susceptibility to VPA toxicity 32-34. VPA exerts numerous documented effects on mitochondrial metabolism. It is metabolized by and inhibits ß-oxidation through several mechanisms 35. VPA and its metabolites sequester coenzyme A (CoA), depleting mitochondrial CoA 36. Furthermore, studies suggest that both unesterified VPA as well as VPA acyl-CoA esters inhibit fatty acid oxidation enzymes 37,38. In addition to affecting ß-oxidation, VPA inhibits α-ketoglutarate dehydrogenase, a key enzyme of the tricarboxylic acid (TCA) cycle 39,40. Inhibition of this enzyme is a proposed mechanism underlying decreased TCA cycle flux in the presence of VPA 41. VPA also decreases levels of carnitine 42,43 , which transpo...

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Section: Introductionmentioning

confidence: 98%

Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae

Salsaa

Pereira

Liu

et al. 2020

Sci Rep

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“…These and other studies have given rise to the ‘selfish brain’ hypothesis of hypertension, which proposes that the brain puts the utmost priority on maintaining its own supply of blood and oxygen at the expense of systemic hypertension (Paton et al . ) [distinct from the ‘selfish brain’ hypothesis of metabolic abnormalities in neurological disorders (Mansur & Brietzke )]. This concept is supported by observations in hypertensive human patients that total CBF was reduced in essential hypertension (Rodriguez et al .…”

Section: The Importance Of the Cerebral Oxygen Supplymentioning

confidence: 87%

Intracranial mechanisms for preserving brain blood flow in health and disease

2016

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The brain is an exceptionally energetically demanding organ with little metabolic reserve, and multiple systems operate to protect and preserve the brain blood supply. But how does the brain sense its own perfusion? In this review, we discuss how the brain may harness the cardiovascular system to counter threats to cerebral perfusion sensed via intracranial pressure (ICP), cerebral oxygenation and ischaemia. Since the work of Cushing over 100 years ago, the existence of brain baroreceptors capable of eliciting increases in sympathetic outflow and blood pressure has been hypothesized. In the clinic, this response has generally been thought to occur only in extremis, to perfuse the severely ischaemic brain as cerebral autoregulation fails. We review evidence that pressor responses may also occur with smaller, physiologically relevant increases in ICP. The incoming brain oxygen supply is closely monitored by the carotid chemoreceptors; however, hypoxia and other markers of ischaemia are also sensed intrinsically by astrocytes or other support cells within brain tissue itself and elicit reactive hyperaemia. Recent studies suggest that astrocytic oxygen signalling within the brainstem may directly affect sympathetic nerve activity and blood pressure. We speculate that local cerebral oxygen tension is a major determinant of the mean level of arterial pressure and discuss recent evidence that this may be the case. We conclude that intrinsic intra- and extra-cranial mechanisms sense and integrate information about hypoxia/ischaemia and ICP and play a major role in determining the long-term level of sympathetic outflow and arterial pressure, to optimize cerebral perfusion.

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“…BDNF), but also include genomic, transcriptomic, metabolomic, and connectomic substrates . A point of convergence is noted, insofar as brain substrates that show (multi‐omic) changes associated with obesity overlap with substrates implicated as subserving cognition …”

Section: Discussionmentioning

confidence: 99%

Adverse effects of obesity on cognitive functions in individuals at ultra high risk for bipolar disorder: Results from the global mood and brain science initiative

et al. 2017

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Individuals at varying degrees of risk for BD exhibit greater cognitive impairment as a function of co-existing overweight/obesity. Prediction models for BD may be substantively informed by including information related to overweight/obesity and, perhaps, other general medical conditions that share pathology with BD. Our findings herein, as well as the salutary effects of bariatric surgery on measures of cognitive function in obese populations, provide the rationale for hypothesizing that mitigating excess weight in individuals at elevated risk for BD may forestall or prevent declaration of illness.

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The "selfish brain" hypothesis for metabolic abnormalities in bipolar disorder and schizophrenia

Cited by 12 publications

References 98 publications

Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae

Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae

Intracranial mechanisms for preserving brain blood flow in health and disease

Adverse effects of obesity on cognitive functions in individuals at ultra high risk for bipolar disorder: Results from the global mood and brain science initiative

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