SODIUM-CHANNEL BLOCKERS REDUCE OXYGEN-GLUCOSE DEPRIVATION-INDUCED CORTICAL NEURONAL INJURY WHEN COMBINED WITH GLUTAMATE-RECEPTOR ANTAGONISTS

Blockers of voltage-gated Na+ channels can protect central neuronal ax ons from hypoxic injury in vitro but have shown limited neuroprotectiv e effects on neurons, where substantial injury is mediated by glutamat e receptors. We explored the ability of several voltage-gated Na+ chan nel blockers to protect murine cultured cortical neurons from injury i nduced by oxygen-glucose deprivation. Whole-cell recordings from neuro ns revealed two types of Na+ currents activated by membrane depolariza tion: one rapidly inactivating and the other noninactivating. Both cur rents were blocked by tetrodotoxin (TTX) and 5,5-diphenylhydantoin (ph enytoin). Fluorescent imaging using the Na+-selective dye SBFI confirm ed that TTX attenuated the increase in intracellular free Na+ induced by oxygen-glucose deprivation. Addition of TTX (1 mu M) but not phenyt oin (10-100 mu M) produced a small and variable reduction in neuronal death subsequent to oxygen-glucose deprivation for 40 to 50 min, Block ade of glutamate neurotoxicity by combined addition of MK-801, 7-chlor okynurenate and 6-cyano-7-nitroquinoxaline-2,3-dione markedly reduced injury such that prolonged deprivation times (75-100 min) were needed to induce widespread neuronal death. In this setting of glutamate rece ptor blockade, addition of mt, phenytoin or one of several other Na+ c hannel blockers-lidocaine (100 mu M), QX-314 (1 mM), quinidine (100 mu M) or lorcainide (10 or 100 mu M)-all further reduced neuronal death. Present results raise the possibility that Na+ channel blockers may b e useful in protecting gray matter from hypoxic-ischemic injury, espec ially when combined with antiexcitotoxic approaches.