Tetraethylammonium exacerbates ischemic neuronal injury in rat cerebrocortical slice cultures.
We investigated potential contribution of K+ channel activity to regulation of ischemia-induced neuronal injury, using cerebrocortical slice cultures. Exposure of cultures to a glucose-free conditioning solution containing sodium azide and 2-deoxyglucose caused neuronal cell death as assessed by cellular uptake of propidium iodide, which was prevented by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist. Application of tetraethylammonium markedly exacerbated ischemic neuronal injury. Charybdotoxin, a blocker of large-conductance Ca(2+)-activated K+ (BK(Ca)) channels, also augmented ischemic injury, whereas AM 92016, a blocker of delayed rectifier K+ channels, and dequalinium, a blocker of small-conductance Ca(2+)-activated K+ channels, had no significant effect. In addition, tetraethylammonium and charybdotoxin were effective in augmenting NMDA-induced neuronal injury. These results present unprecedented evidence for the ability of tetraethylammonium to enhance ischemic neuronal death, and suggest that BK(Ca) channels constitute an endogenous system to protect cortical neurons from ischemic injury, via prevention of NMDA receptor over-activation.
Katsuki
Hiroshi
H
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Shinohara
Atsumi
A
Fujimoto
Shinji
S
Kume
Toshiaki
T
Akaike
Akinori
A
D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000503:physiopathology*; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D018999:Charybdotoxin / Q000494:pharmacology; D003868:Dequalinium / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D013015:Sotalol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology*; D013997:Time Factors
D018696:Neuroprotective Agents; D018999:Charybdotoxin; C102243:AM 92016; D016202:N-Methylaspartate; D019789:Tetraethylammonium; D016291:Dizocilpine Maleate; D013015:Sotalol; D003868:Dequalinium