Protection of cortical neurons against oxygen-glucose deprivation and N-methyl-D-aspartate by DIDS and SITS

The Cl- channel blockers, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) or 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) dose-dependently protected against oxygen-glucose deprivation in cultured rat cortical neurons. DIDS or SITS attenuated oxygen-glucose deprivation-induced increases in extracellular glutamate concentrations and intracellular Ca2+. DIDS or SITS provided moderate protection against N-methyl-D-aspartate (NMDA) toxicity and decreased NMDA receptor-mediated increases in intracellular Ca2+. Whole-cell NMDA receptor currents were attenuated 39 +/- 2% and 21 +/- 3% by 1 mM DIDS and SITS, respectively. Other Cl- channel blockers as equipotent as DIDS and SITS did not decrease oxygen-glucose deprivation- or NMDA-mediated neuronal Ca2+ influx or toxicity. Neurotoxicity by exogenous glutamate was not prevented by SITS and was exacerbated by DIDS. Reductions in oxygen-glucose deprivation-induced increases in intracellular Ca2+ levels underlie neuroprotection by DIDS and SITS. This was a reflection of lower extracellular [glutamate], direct inhibition of Ca2+ influx through postsynaptic NMDA receptors, and possibly through other protective properties associated with DIDS and SITS. (C) 2003 Elsevier Science B.V. All rights reserved.