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 Ca(2+). DIDS or SITS provided moderate protection against N-methyl-D-aspartate (NMDA) toxicity and decreased NMDA receptor-mediated increases in intracellular Ca(2+). 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 Ca(2+) 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 Ca(2+) levels underlie neuroprotection by DIDS and SITS. This was a reflection of lower extracellular [glutamate], direct inhibition of Ca(2+) influx through postsynaptic NMDA receptors, and possibly through other protective properties associated with DIDS and SITS.
Tauskela
Joseph S
JS
Institute for Biological Sciences, National Research Council of Canada, Montreal Road Campus, Building M-54, K1A 0R6, Ottawa, ON, Canada. joe.tauskela@nrc.ca
Mealing
Geoff
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Comas
Tanya
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Brunette
Eric
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Monette
Robert
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Small
Daniel L
DL
Morley
Paul
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D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology*; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000494:pharmacology*; D000693:Anaerobiosis; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology / Q000633:toxicity; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology* / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010100:Oxygen / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D005947:Glucose; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D010100:Oxygen; D002118:Calcium