Valproate and 4-methyloctanoic acid, an analogue of valproate, in animal models of epilepsy

Valproic acid (VPA) is a commonly used drug for the treatment of epilepsy, bipolar disorder and migraine, yet its mechanisms of action are unknown. The neuroprotective effect of VPA has been hypothesized to be secondary to inhibition of the cAMP/protein kinase A (PKA) pathway. Here, the result show that VPA (1mM) inhibited mossy fibre long-term potentiation induced (LTP) by application of high frequency stimulation in dentate gyrus. Furthermore, VPA (1mM) inhibited enhancement of mossy fibre responses induced by application of forskolin (50 μM), consistent with an effect on the PKA pathway. Using biochemical assays, it was further demonstrated that this was not due to a direct effect on PKA, but resulted from inhibition of adenylyl cyclase. The results further show using in vitro seizure models (Pentylenetetrazole model and low- Mg2+ model) that this mechanism cannot fully explain VPA’s anti-seizure effect, but rather, by modifying synaptic plasticity, it may be more important for VPA’s antiepileptogenic and neuroprotective action. VPA therefore has distinct mechanisms of action that contribute to its diverse biological activity. In hippocampi from epileptic rats (following pilocarpine-induced status epilepticus), but not in control tissue, VPA affects short-term plasticity, indicating that VPA may have specific effects in epileptic rather than control animals. Using in vitro seizure models (Pentylenetetrazole model and low-Mg2+ model) and an in vivo status epilepticus model (the perforant pathway stimulation model), 4- methyloctanoic acid is further established that it is a more potent antiepileptic drug than VPA and provides neuroprotective effects which are similar to VPA. Furthermore, 4- methyloctanoic acid (1mM) inhibited enhancement of mossy fibre responses induced by application of forskolin (50 μM), indicating that 4-methyloctanoic acid shares the same effect as VPA on modulation of PKA.