The epsilon theory: a novel synthesis of the underlying molecular and electrophysiological mechanisms of primary generalized epilepsy and the possible mechanism of action of valproate

Primary generalized epilepsy may be the result of maldevelopment of central nervous system and each seizure may be the consequence of a neuronal maladaptation to an unknown stimulus using the paleospinothalamical tract due to an overexpression of brain-derived neurotrophic factor and neurotrophin-3. The subsequent protein kinase C ϵ (PKC-ϵ) activation and intracellular Ca2+ release causes a nociceptive hypersensitization and an increased cortical hyperexcitability because of increased frequency of synchronous Ca2+ oscillations, cortical maldevelopment at the level of synapses and an attenuation of GABAA receptor mediated responses in reticular thalamic nucleus. Valproate may exert its antiepileptic effect as a PKC-ϵ inhibitor, and using with a PKC-ϵ activator that cannot pass blood brain barrier, its side effects may become avoidable.