MOOD STABILIZERS TARGET THE BRAIN ARACHIDONIC ACID CASCADE? Administration to rats at therapeutically relevant doses of each of the FDA-approved mood stabilizers -- lithium, valproate, carbamazepine, and lamotrigine -- downregulated brain arachidonic acid (AA) metabolic markers but not docosahexaenoic acid markers. The first three agents, which are preferred for treating bipolar mania, decreased turnover of AA in brain phospholipids, expression of cyclooxygenase (COX)-2 and AA-selective cytosolic phospholipase A2 or acyl-CoA synthetase, and the concentration of prostaglandin E2. Lamotrigine, preferred for bipolar depression, downregulated COX-2 transcription and activity. These studies lend further support to our hypothesis that the brain AA cascade is the common target of effective mood stabilizers, and suggest that measuring AA cascade markers in the rat can be used to screen for new, less-toxic, bipolar disorder agents (Rao et al. 2008; Lee et al. 2007, Lee et al. 2008).? ? MOOD STABILIZERS UPREGULATE EXPRESSION OF BRAIN NEUROTROPHIC FACTORS? Brain derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2) are involved in neuronal signaling, cell survival and plasticity. Decreased brain levels of these factors occur in bipolar disorder. We showed that chronic administration to rats of lithium, valproic acid, carbamazepine, or lamotrigine, to produce therapeutically relevant plasma concentrations, increased BDNF and Bcl-2 levels in the cytosolic fraction of the frontal cortex. This common effect of the mood stabilizers on brain neuroprotective factors may be mediated by downregulation of arachidonic acid metabolism (Chang et al. In press).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000145-08
Application #
7732145
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2008
Total Cost
$490,260
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Modi, Hiren R; Ma, Kaizong; Chang, Lisa et al. (2017) Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder. Psychiatry Res 254:279-283
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
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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
Lee, Ho-Joo; Rao, Jagadeesh S; Rapoport, Stanley I et al. (2007) Antimanic therapies target brain arachidonic acid signaling: lessons learned about the regulation of brain fatty acid metabolism. Prostaglandins Leukot Essent Fatty Acids 77:239-46
Rao, Jagadeesh S; Ertley, Renee N; Rapoport, Stanley I et al. (2007) Chronic NMDA administration to rats up-regulates frontal cortex cytosolic phospholipase A2 and its transcription factor, activator protein-2. J Neurochem 102:1918-27

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