Trans‐2‐ene‐valproic acid is less behaviorally teratogenic than an equivalent dose of valproic acid in rats

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Abstract
Although animal experiments have shown the trans‐2‐ene metabolite (t‐2‐ene‐VPA) of valproic acid (VPA) to be pharmacologically equivalent to the parent compound in terms of anticonvulsant activity, it is considerably less teratogenic in studies which have examined prenatally exposed fetuses for morphological defects. This has made t‐2‐ene‐VPA an attractive potential antiepileptic agent. However, while neurobehavioral alterations have also been observed in rats prenatally exposed to VPA, even at doses below those which produce malformations, the developmental neurotoxicity of t‐2‐ene‐VPA had not previously been examined. The current study evaluated the long‐term behavioral effects of prenatal exposure to t‐2‐ene‐VPA. Pregnant CD rats were treated with 300 or 400 mg/kg t‐2‐ene‐VPA by gavage on days 7–18 of gestation, doses previously shown to produce no teratogenicity. A VPA group was administered 300 mg/kg for comparison. The pharmacokinetic profiles of the two compounds were similar. Behavioral findings in offspring prenatally exposed to VPA were consistent with previous findings, i.e., VPA offspring exhibited decreased locomotor activity, increased swimming maze errors, and reduced tactile startle responding compared to controls. In the 400 mg/kg t‐2‐ene‐VPA group, Cincinnati maze errors and auditory startle reactivity were increased, while no significant behavioral effects were detected in the 300 mg/kg t‐2‐ene group. These results indicate that the developmental neurotoxicity of t‐2‐ene‐VPA is lower than that of VPA but is still significant.