Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients.
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 A(2) (cPLA(2)) IVA, secretory sPLA(2) 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 Ca(2+)-independent iPLA(2)VIA, 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.
Kim
H-W
HW
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Rapoport
S I
SI
Rao
J S
JS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016718:Arachidonic Acid / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000235:genetics; D001714:Bipolar Disorder / Q000473:pathology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002465:Cell Movement / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D054510:Phospholipases A2, Cytosolic / Q000235:genetics / Q000378:metabolism; D054497:Phospholipases A2, Secretory / Q000235:genetics / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism; D011180:Postmortem Changes; D000071876:Prostaglandin-E Synthases; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism; D013223:Statistics as Topic; D015854:Up-Regulation / Q000502:physiology*
D051127:Scavenger Receptors, Class E; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D054510:Phospholipases A2, Cytosolic; D054497:Phospholipases A2, Secretory; D010751:Phosphopyruvate Hydratase; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases