BLOCK OF THE RAT-BRAIN IIA SODIUM-CHANNEL ALPHA-SUBUNIT BY THE NEUROPROTECTIVE DRUG RILUZOLE

The effects of riluzole, a novel neuroprotective drug with anticonvuls ant and anti-ischemic properties, were studied on currents carried by cloned rat brain IIA sodium channel cu subunits expressed in Xenopus o ocytes. (i) When the oocytes were held at strongly hyperpolarized pote ntials to close the sodium channels and riluzole was added to the exte rnal solution, the current elicited by test depolarizing pulses was re duced within a few minutes and recovered upon washout of the riluzole. Although the currents were reduced, riluzole did not shift the peak c urrent-voltage relationship. An inhibitory constant of 30 mu M was est imated for the low affinity block of closed channels. (ii) Riluzole di d not affect the time course of inactivation, and repetitive stimulati on at frequencies that did not result in significant accumulation of i nactivation did not affect current block. These results suggest that r iluzole did not block open channels. (iii) Riluzole increased steady s tate inactivation by shifting its voltage dependence in the hyperpolar izing direction, by prolonging the recovery from inactivation, and by blocking more effectively at high stimulation frequencies. According t o the modulated receptor theory, these results suggest that riluzole b inds selectively to inactivated channels, with an inhibitory constant estimated at 0.2 mu M These results show that the riluzole binding sit e is on the alpha subunit of the sodium channel, and they suggest that stabilization of the inactivated state may underlie the neuroprotecti ve properties of riluzole.