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 axons from hypoxic injury in vitro but have shown limited neuroprotective effects on neurons, where substantial injury is mediated by glutamate receptors. We explored the ability of several voltage-gated Na+ channel blockers to protect murine cultured cortical neurons from injury induced by oxygen-glucose deprivation. Whole-cell recordings from neurons revealed two types of Na+ currents activated by membrane depolarization: one rapidly inactivating and the other noninactivating. Both currents were blocked by tetrodotoxin (TTX) and 5,5-diphenylhydantoin (phenytoin). Fluorescent imaging using the Na(+)-selective dye SBFI confirmed that TTX attenuated the increase in intracellular free Na+ induced by oxygen-glucose deprivation. Addition of TTX (1 microM) but not phenytoin (10-100 microM) produced a small and variable reduction in neuronal death subsequent to oxygen-glucose deprivation for 40 to 50 min. Blockade of glutamate neurotoxicity by combined addition of MK-801, 7-chlorokynurenate 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 receptor blockade, addition of TTX, phenytoin or one of several other Na+ channel blockers--lidocaine (100 microM), QX-314 (1 mM), quinidine (100 microM) or lorcainide (10 or 100 microM)--all further reduced neuronal death. Present results raise the possibility that Na+ channel blockers may be useful in protecting gray matter from hypoxic-ischemic injury, especially when combined with antiexcitotoxic approaches.
Lynch
J J
JJ
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Yu
S P
SP
Canzoniero
L M
LM
Sensi
S L
SL
Choi
D W
DW
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D005947:Glucose