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 epsilon (PKC-epsilon) activation and intracellular Ca(2+) release causes a nociceptive hypersensitization and an increased cortical hyperexcitability because of increased frequency of synchronous Ca(2+) oscillations, cortical maldevelopment at the level of synapses and an attenuation of GABA(A) receptor mediated responses in reticular thalamic nucleus. Valproate may exert its antiepileptic effect as a PKC-epsilon inhibitor, and using with a PKC-epsilon activator that cannot pass blood brain barrier, its side effects may become avoidable.
Toth
Marton
M
Centre for Postgraduate Education, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary. toth_martin@yahoo.com
D002118:Calcium / Q000378:metabolism; D002490:Central Nervous System / Q000503:physiopathology*; D004829:Epilepsy, Generalized / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology*; D006801:Humans; D009414:Nerve Growth Factors / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D014635:Valproic Acid / Q000378:metabolism / Q000627:therapeutic use*
D009414:Nerve Growth Factors; D014635:Valproic Acid; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D002118:Calcium