Abstract | BACKGROUND: Mood stabilizers used for treating bipolar disorder (BD) selectively downregulate arachidonic acid (AA) turnover (deacylation-reacylation) in brain phospholipids, when given chronically to rats. In vitro studies suggest that one of these, valproic acid (VPA), which is teratogenic, reduces AA turnover by inhibiting the brain long-chain acyl-CoA synthetase (Acsl)4 mediated acylation of AA to AA- CoA. We tested whether non-teratogenic VPA analogues might also inhibit Acsl4 catalyzed acylation, and thus have a potential anti-BD action. METHODS: RESULTS: Acsl4-mediated conversion of AA to AA- CoA in vitro was inhibited uncompetitively by PIA, with a Ki of 11.4mM compared to a published Ki of 25mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect. CONCLUSIONS: PIA's ability to inhibit conversion of AA to AA- CoA by Acsl4 in vitro suggests that, like VPA, PIA may reduce AA turnover in brain phospholipids in unanesthetized rats, and if so, may be effective as a non-teratogenic mood stabilizer in BD patients.
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Authors | Hiren R Modi, Mireille Basselin, Ameer Y Taha, Lei O Li, Rosalind A Coleman, Meir Bialer, Stanley I Rapoport |
Journal | Biochimica et biophysica acta
(Biochim Biophys Acta)
Vol. 1831
Issue 4
Pg. 880-6
(Apr 2013)
ISSN: 0006-3002 [Print] Netherlands |
PMID | 23354024
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Published by Elsevier B.V. |
Chemical References |
- Antimanic Agents
- Arachidonic Acid
- Valproic Acid
- Acsl4 protein, rat
- Coenzyme A Ligases
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Topics |
- Acylation
(drug effects)
- Animals
- Antimanic Agents
(chemistry, pharmacology)
- Arachidonic Acid
(metabolism)
- Bipolar Disorder
(metabolism)
- Coenzyme A Ligases
(metabolism)
- Molecular Structure
- Rats
- Valproic Acid
(chemistry, pharmacology)
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