ALTERED NA-CHANNEL FUNCTION AS AN IN-VITRO MODEL OF THE ISCHEMIC PENUMBRA - ACTION OF LUBELUZOLE AND OTHER NEUROPROTECTIVE DRUGS()

Veratridine blocks Na+-channel inactivation and causes a persistant Na +-influx. Exposure of hippocampal slices to 10 mu M veratridine led to a failure of synaptic transmission, repetitive spreading depression ( SD)-like depolarizations of increasing duration, loss of Ca+-homeostas is, a large reduction of membrane potential, spongious edema and metab olic failure. Normalization of the amplitude of the negative DC shift evoked by high K+ ACSF 80 min after veratridine exposure was taken as the primary endpoint for neuroprotection. Compounds whose mechanism of action includes Na+-channel modulation were neuroprotective (IC50-val ues in mu M): tetrodotoxin 0.017, verapamil 1.18, riluzole 1.95, lamot rigine greater than or equal to 10, and diphenylhydantoin 16.1. Both N MDA (MK-801 and APH) and non-NMDA (NBQX) excitatory amino acid antagon ists were inactive, as were NOS-synthesis inhibitors (nitro-L-arginine and L-NAME), Ca2+-channel blockers (cadmium, nimodipine), and a K+-ch annel blocker (TEA). Lubeluzole significantly delayed the time before the slices became epileptic, postponed the first SD-like depolarizatio n, allowed the slices to better recover their membrane potential after a larger number of SD-like DC depolarizations, preserved Ca2+ and ene rgy homeostasis, and prevented the neurotoxic effects of veratridine ( IC50-value 0.54 mu M). A concentration of lubeluzole, which was 40 X h igher than its IC50-value for neuroprotection against veratridine, had no effect on repetitive Na+-dependent action potentials induced by de polarizing current in normal ACSF. The ability of lubeluzole to preven t the pathological consequences of excessive Na+-influx, without alter ing normal Na+-channel function may be of benefit in stroke.