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

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 (Acs1-4) 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-C-14] AA in unanaesthetized rats for 10 min, and measuring labeled and unlabeled lipids in plasma and highenergy microwaved brain. Results: VCD, compared with vehicle, increased lambda, 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.