Hippocampal slices: glutamate overflow and cellular damage from ischemia are reduced by sodium-channel blockade.
We evaluated concentrations of excitatory amino acids released from slices into the superfusing solution and also evaluated extracellular field potential recordings and histological appearance of slice tissues to evaluate several sodium-channel modulating drugs as potential treatments for ischemia. The selective sodium-channel blocker tetrodotoxin (TTX, 1 microM) reduced glutamate release from deprivation of oxygen and D-glucose, while calcium-channel blockade was ineffective. Thus, during ischemia, we propose that glutamate may be released from the free cytosolic pool ('metabolic' glutamate) rather than by exocytosis. TTX (100-500 nM) and voltage-dependent sodium-channel blockers (phenytoin, 20-100 microM; lidocaine, 2-200 microM) each prevented damage to slices without blocking action potentials. The reduction of cellular depolarization and sodium loading during ischemia may explain the neuroprotective action of several sodium-channel modulating drugs in our in vitro studies and also in animal models.
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004594:Electrophysiology; D018698:Glutamic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D010672:Phenytoin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin / Q000494:pharmacology*; D013997:Time Factors
D026941:Sodium Channel Blockers; D018698:Glutamic Acid; D013779:Tetrodotoxin; D010672:Phenytoin