The present study investigated the effects of RS-100642-198 (a novel
sodium channel blocker), and two related compounds (
mexiletine and
QX-314), in in vitro models of neurotoxicity. Neurotoxicity was produced in primary cerebellar cultures using
hypoxia/
hypoglycemia (H/H),
veratridine or
glutamate where, in vehicle-treated neurons, 65%, 60% and 75% neuronal injury was measured, respectively. Dose-response neuroprotection experiments were carried out using concentrations ranging from 0.1-500 micro M. All the
sodium channel blockers were neuroprotective against H/H-induced injury, with each exhibiting similar potency and efficacy. However, against
veratridine-induced neuronal injury only RS-100642-198 and
mexiletine were 100% protective, whereas
QX-314 neuroprotection was limited (i.e. only 54%). In contrast, RS-100642-198 and
mexiletine had no effect against
glutamate-induced injury, whereas
QX-314 produced a consistent, but very limited (i.e. 25%), neuroprotection. Measurements of intraneuronal
calcium [Ca(2+)]i) mobilization revealed that
glutamate caused immediate and sustained increases in [Ca(2+)]i which were not affected by RS-100642-198 or
mexiletine. However, both drugs decreased the initial amplitude and attenuated the sustained rise in [Ca(2+)]i mobilization produced by
veratridine or KCl depolarization.
QX-314 produced similar effects on
glutamate-,
veratridine- or KCl-induced [Ca(2+)]i dynamics, effectively decreasing the amplitude and delaying the initial spike in [Ca(2+)]i, and attenuating the sustained increase in [Ca(2+)]i mobilization. By using different in vitro models of excitotoxicity, a heterogeneous profile of
neuroprotective effects resulting from
sodium channel blockade has been described for RS-100642-198 and related drugs, suggesting that selective blockade of neuronal
sodium channels in pathological conditions may provide therapeutic neuroprotection against depolarization/excitotoxicity via inhibition of voltage-dependent Na(+) channels.