Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder. (August 2017)

• Record Type: Journal Article
• Authors: Modi, Hiren R.; Ma, Kaizong; Chang, Lisa; Chen, Mei; Rapoport, Stanley I.
• Is Part Of: Psychiatry research. Volume 254(2017)
• Page Start: 279
• Page End: 283
• Publication Date: 2017-08
• Subjects: AA arachidonic acid -- AA-CoA arachidonoyl-CoA -- VPA Valproic acid -- VCD Valnoctamide -- ChoGpl choline glycerophospholipid -- cPLA2 cytosolic phospholipase A2, EtnGpl, ethanolamine glycerophospholipid -- FAME fatty acid methyl esters -- PtdIns phosphatidylinositol -- PtdSer phosphatidylserine -- DHA docosahexaenoic acid -- EPA eicosapentaenoic acid -- PUFA polyunsaturated fatty acid -- BD bipolar disorder; Valnoctamide -- Bipolar -- Valproic -- Arachidonic acid -- Rat; Psychiatry -- Periodicals; Psychiatry -- periodicals; Psychiatrie -- Périodiques; 616.89
• DOI: 10.1016/j.psychres.2017.04.048
• Languages: English
• ISSNs: 0165-1781

Abstract

Abstract: Background: Valproic acid (VPA), used for treating bipolar disorder (BD), is teratogenic by inhibiting histone deacetylase. In unanaesthetized rats, chronic VPA, like other mood stabilizers, reduces arachidonic acid (AA) turnover in brain phospholipids, and inhibits AA activation to AA-CoA by recombinant acyl-CoA synthetase-4 (Acsl-4) in vitro . Valnoctamide (VCD), a non-teratogenic constitutional isomer of VPA amide, reported effective in BD, also inhibits recombinant Acsl-4 in vitro . Hypothesis: VCD like VPA will reduce brain AA turnover in unanaesthetized rats. Methods: A therapeutically relevant (50 mg/kg i.p.) dose of VCD or vehicle was administered daily for 30 days to male rats. AA turnover and related parameters were determined using our kinetic model, following intravenous [1- 14 C]AA in unanaesthetized rats for 10 min, and measuring labeled and unlabeled lipids in plasma and high-energy microwaved brain. Results: VCD, compared with vehicle, increased λ, the ratio of brain AA-CoA to unesterified plasma AA specific activities; and decreased turnover of AA in individual and total brain phospholipids. Conclusions: VCD's ability like VPA to reduce rat brain AA turnover and inhibit recombinant Acsl-4, and its efficacy in BD, suggest that VCD be further considered as a non-teratogenic VPA substitute for treating BD. Highlights: Arachidonic acid (AA) turnover was measured in brain phospholipids of awake rats treated with valnoctamide (VCD). VCD is a nonteratogenic isomer of teratogenic valproic acid (VPA), that is effective in bipolar disorder (BD). Like VPA, VCD reduced AA turnover and increased AA dilution factor λ (ratio brain AA-CoA to plasma AA specific activity). VCD and VPA also reported to inhibit recombinant acyl-CoA synthetase-4 (Acsl-4), which regulates AA turnover. Similar actions of VCD and VPA on AA suggest that VCD and other nonteratogenic Acsl-4 inhibitors be tested for BD.