Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid,uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: A potential drug for bipolar disorder |
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Authors: | Hiren R. Modi Mireille Basselin Ameer Y. Taha Lei O. Li Rosalind A. Coleman Meir Bialer Stanley I. Rapoport |
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Affiliation: | 1. Brain Physiology and Metabolism Section, National Institute on Aging, Laboratory of Neurosciences, National Institutes of Health, Bethesda, MD, USA;2. Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA;3. Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel |
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Abstract: | BackgroundMood 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.MethodsRat Acsl4-flag protein was expressed in Escherichia coli, and the ability of three VPA analogues, propylisopropylacetic acid (PIA), propylisopropylacetamide (PID) and N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (MTMCD), and of sodium butyrate, to inhibit conversion of AA to AA-CoA by Acsl4 was quantified using Michaelis–Menten kinetics.ResultsAcsl4-mediated conversion of AA to AA-CoA in vitro was inhibited uncompetitively by PIA, with a Ki of 11.4 mM compared to a published Ki of 25 mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect.ConclusionsPIA'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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Keywords: | AA, arachidonic acid Acsl, acyl-CoA synthetase BD, bipolar disorder MTMCD, N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide PIA, propylisopropylacetic acid PID, propylisopropylacetamide VPA, valproic acid |
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