Actions of the novel neuroprotective agent, lifarizine (RS‐87476), on voltage‐dependent sodium currents in the neuroblastoma cell line, N1E‐115

1 The actions of the neuroprotective agent, lifarizine (RS‐87476‐190), on voltage‐dependent Na+ currents have been examined in the neuroblastoma cell line, N1E‐115, using the whole‐cell variant of the patch clamp technique. 2 At a holding potential of −80 mV, lifarizine reduced the peak Na+ current evoked by a 10 ms depolarizing step with an IC50 of 1.3μm. At holding potentials of −100 and −60mV the IC50 concentrations of lifarizine were 7.3 μm and 0.3μm, respectively. 3 At a holding potential of −100 mV, most channels were in the resting state and the IC50 value for inhibition of Na+ current should correspond to the dissociation constant of lifarizine for resting channels (KR). Kr was therefore estimated to be 7.3 μm. 4 In the absence of lifarizine, recovery from inactivation following a 20 s depolarization from −100 mV to 0 mV was complete within 2 s. However, in the presence of 3 μm lifarizine recovery took place in a biexponential fashion with time constants of 7 s and 79 s. 5 Lifarizine (1 μm) had no effect on steady‐state inactivation curves when conditioning pre‐pulses of 1 s duration were used. However, when pre‐pulse durations of 1 min were used the curves were shifted to the left by lifarizine by about 10 mV. Analysis of the shifts induced by a range of lifarizine concentrations revealed that the apparent affinity of lifarizine for the inactivated state of the channel (KI) was 0.19 μm. 6 Lifarizine (1 μm) had no effect on chloramine‐T‐modified Na+ currents, suggesting no significant open channel interaction. 7 Taken together, these data show that lifarizine is a potent voltage‐dependent inhibitor of Na+ currents in N1E‐115 cells and that the voltage‐dependence arises from an interaction of the compound with the inactivated state of the channel. The possible contribution of Na+ current inhibition to the neuroprotective actions of lifarizine is discussed.