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Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients

Abstract

Mood stabilizers that are approved for treating bipolar disorder (BD), when given chronically to rats, decrease expression of markers of the brain arachidonic metabolic cascade, and reduce excitotoxicity and neuroinflammation-induced upregulation of these markers. These observations, plus evidence for neuroinflammation and excitotoxicity in BD, suggest that arachidonic acid (AA) cascade markers are upregulated in the BD brain. To test this hypothesis, these markers were measured in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. Mean protein and mRNA levels of AA-selective cytosolic phospholipase A2 (cPLA2) IVA, secretory sPLA2 IIA, cyclooxygenase (COX)-2 and membrane prostaglandin E synthase (mPGES) were significantly elevated in the BD cortex. Levels of COX-1 and cytosolic PGES (cPGES) were significantly reduced relative to controls, whereas Ca2+-independent iPLA2VIA, 5-, 12-, and 15-lipoxygenase, thromboxane synthase and cytochrome p450 epoxygenase protein and mRNA levels were not significantly different. These results confirm that the brain AA cascade is disturbed in BD, and that certain enzymes associated with AA release from membrane phospholipid and with its downstream metabolism are upregulated. As mood stabilizers downregulate many of these brain enzymes in animal models, their clinical efficacy may depend on suppressing a pathologically upregulated cascade in BD. An upregulated cascade should be considered as a target for drug development and for neuroimaging in BD.

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Acknowledgements

We thank the Harvard Brain Bank, Boston, MA for providing the postmortem brain samples under PHS Grant number R24MH068855. This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. We also thank the Fellows' Editorial Board at NIH for reviewing the manuscript.

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Kim, HW., Rapoport, S. & Rao, J. Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients. Mol Psychiatry 16, 419–428 (2011). https://doi.org/10.1038/mp.2009.137

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