Valproic Acid

Valproic acid is an analog of the natural fatty acid valeric acid that inhibits class I histone deacetylases (HDACs) with IC₅₀ values of approximately 2 mM.¹ It decreases the number of axon branches in sensory neurons isolated from newborn rat dorsal root ganglia, an effect that is reversed by inositol-1,4,5-trisphosphate (1,4,5-IP₃).² In vivo, valproic acid inhibits amyloid-β deposition and neuritic plaque formation and decreases escape latency in Morris water maze, indicating improved memory performance, in the APP23 transgenic mouse model of Alzheimer's disease.³ Valproic acid has anticonvulsant activity in the pentylenetetrazole seizure threshold test in mice (ED₅₀ = 0.71 mmol/kg) but induces neurotoxicity when administered at doses greater than or equal to 1.2 mmol/kg.⁴ Formulations containing valproic acid have been used in the treatment of bipolar disorder and various seizure disorders.

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1. Göttlicher, M., Minucci, S., Zhu, P., et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20(24), 6969-6978 (2001).

2. Williams, R.S.B., Cheng, L., Mudge, A.W., et al. A common mechanism of action for three mood-stabilizing drugs. Nature 417(6886), 292-295 (2002).

3. Qing, H., He, G., Ly, P.T., et al. Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models. J. Exp. Med. 205(12), 2781-2789 (2008).

4. Elmazar, M.M., Hauck, R.S., and Nau, H. Anticonvulsant and neurotoxic activities of twelve analogues of valproic acid. J. Pharm. Sci. 82(12), 1255-1258 (1993).