CURRENT LITERATURE CHANGING CHANNELS: MECHANISMS AND RESPONSIVENESS TO ANTIEPILEPTIC DRUGS IN CHRONIC EPILEPSY Anticonvulsant Pharmacology of Voltage-gated Na+ Channels in Hippocampal Neurons of Control and Chronically Epileptic Rats

Voltage-gated Na + channels are a main target of many first-line anticonvulsant drugs, and their mechanism of action has been extensively investigated in cell lines and native neurons. Nevertheless, it is unknown whether the efficacy of these drugs might be altered after chronic epileptogenesis. We have, therefore, analyzed the effects of phenytoin (PHT; 100 µM), lamotrigine (LTG; 100 µM), and valproate (VPA; 600 µM) on Na + currents in dissociated rat hippocampal granule neurons in the pi-locarpine model of chronic epilepsy. In control animals, all three substances exhibited modest tonic blocking effects on Na + channels in their resting state. These effects of PHT and LTG were reduced (by 77% and 64%) in epileptic compared with control animals. PHT and VPA caused a shift in the voltage dependence of fast inac-tivation in a hyperpolarizing direction, whereas all three substances shifted the voltage dependence of activation in a depolarizing direction. The anticonvulsant effects on Na + channel voltage dependence proved to be similar in control and epileptic animals. The time course of fast recovery from inactivation was potently slowed by LTG and PHT in control animals, whereas VPA had no effect. Interestingly, the effects of PHT on fast recovery from in-activation were significantly reduced in chronic epilepsy. Taken together, these results reveal that different AEDs may exert a distinct pattern of effects on native Na + channels. Furthermore, the reduction of PHT and, to a less pronounced extent, LTG effects in chronic epilepsy raises the possibility that reduced pharmacosensitivity of Na + channels may contribute to the development of drug resistance. COMMENTARY I t is estimated that ∼30% of epilepsy patients do not respond adequately to currently available medication (1). Individuals with localization-related seizures of hippocampal original appear most at risk (2). Two schools of thought have arisen in an attempt to explain the phenomenon of therapeutic failure in this population. The pharmacokinetic hypothesis suggests that antiepileptic drugs (AEDs) do not reach the epileptic focus in sufficient concentration, possibly because of active efflux that is mediated by locally overexpressed drug-transporter proteins (3). The pharmacodynamic theory proposes a seizure-associated reduction in pharmacologic sensitivity of the ion channels and neurotransmitter receptors that represent the molecular targets of AEDs. Remy and colleagues have conducted an elegant series of experiments that address this latter proposition. The research follows their earlier studies (4), which demonstrated the abolition of carbamazepine (CBZ) effects in isolated neurons taken from …