(1) Chronic lithium administration reduced arachidonic acid turnover in rat brain phospholipids by 80%, without affecting turnover of docosahexaenoic or palmitic acid. The brain concentration of arachidonoyl-CoA, the precursor for arachidonic acid incorporation into phospholipids, was reduced by 50%. Lithium also reduced mRNA and protein levels and enzyme activity of an arachidonate selective cytosolic phospholipase A2 (cPLA2), which releases arachidonic acid from phospholipids during receptor-mediated signal transduction. cPLA2 and the arachidonic acid cascade may be a target of lithium in the treatment of bipolar disorder. (2) Rats were chronically administered valproic acid, an anticonvulsant used to treat bipolar disorder. Arachidonic acid turnover within brain phospholipids was reduced by 30%, but cPLA2 protein was unchanged. Both valproate and lithium may act against bipolar disorder by inhibiting brain arachidonate turnover, lithium by targeting cPLA2, valproate by an as yet unknown mechanism. (3) 1H-magnetic resonance spectroscopy (MRS) showed an elevated brain myoinositol concentration in the trisomy 65Dn mouse, a model for Down syndrome (trisomy 21). A similar reduction in brain myoinositol was reported in Down syndrome. Chronic lithium treatment further reduced brain myoinositol in the mouse, consistent with a hypothesis that lithium inhibits brain inositol monophosphatase and the phosphatidylinositol cycle. (4) A mass spectrometry method was developed and used to show that turnover of myoinositol in phosphatidylinositol of cultured fetal mouse neurons was quite rapid, 10.3% per hour. The spectrometric method with an accompanying mathematical model can also quantify myoinositol turnover in the rodent brain in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000145-01
Application #
6521733
Study Section
(BPMS)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Yuan, Zhi-Xin; Rapoport, Stanley I (2015) Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice. Prostaglandins Leukot Essent Fatty Acids 101:9-14
Modi, Hiren R; Basselin, Mireille; Rapoport, Stanley I (2014) Valnoctamide, a non-teratogenic amide derivative of valproic acid, inhibits arachidonic acid activation in vitro by recombinant acyl-CoA synthetase-4. Bipolar Disord 16:875-80
Modi, Hiren R; Taha, Ameer Y; Kim, Hyung-Wook et al. (2013) Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability. J Neurochem 124:376-87
Kim, H-W; Rapoport, S I; Rao, J S (2011) Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients. Mol Psychiatry 16:419-28
Cheon, Yewon; Park, Jee-Young; Modi, Hiren R et al. (2011) Chronic olanzapine treatment decreases arachidonic acid turnover and prostaglandin Eâ‚‚ concentration in rat brain. J Neurochem 119:364-76
Rapoport, Stanley I; Basselin, Mireille; Kim, Hyung-Wook et al. (2009) Bipolar disorder and mechanisms of action of mood stabilizers. Brain Res Rev 61:185-209
Rao, Jagadeesh S; Rapoport, Stanley I; Kim, Hyung-Wook (2009) Decreased GRK3 but not GRK2 expression in frontal cortex from bipolar disorder patients. Int J Neuropsychopharmacol 12:851-60
Rao, Jagadeesh S; Rapoport, Stanley I (2009) Mood-stabilizers target the brain arachidonic acid cascade. Curr Mol Pharmacol 2:207-14
Chang, Yunyoung C; Kim, Hyung-Wook; Rapoport, Stanley I et al. (2008) Chronic NMDA administration increases neuroinflammatory markers in rat frontal cortex: cross-talk between excitotoxicity and neuroinflammation. Neurochem Res 33:2318-23
Lee, Ho-Joo; Rao, Jagadeesh S; Chang, Lisa et al. (2007) Chronic lamotrigine does not alter the turnover of arachidonic acid within brain phospholipids of the unanesthetized rat: implications for the treatment of bipolar disorder. Psychopharmacology (Berl) 193:467-74

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