Effects of the sodium channel blocker tetrodotoxin (TTX) on cellular ion homeostasis in rat brain subjected to complete ischemia.
Anoxic depolarization (AD) and failure of the cellular ion homeostasis are suggested to play a key role in ischemia-induced neuronal death. Recent studies show that the blockade of Na+ influx significantly improved the neuronal outcome. In the present study, we investigated the effects of 10 microM tetrodotoxin (TTX) on ischemia-induced disturbances of ion homeostasis in the isolated perfused rat brain. TTX inhibited the spontaneous EEG activity, delayed the ischemia-induced tissue acidification, and significantly postponed the occurrence of AD by 65%. The [Ca2+]e elevation prior to AD was attenuated from 17.8% to 6% while the increase of the [Na+]e in this period was enhanced (from 2.9% to 7.3%). These findings implied that the ischemia-induced early cellular sodium load and the corresponding shrinkage of the extracellular space was counteracted by TTX. Our results suggest that the Na+ influx via voltage-dependent channels preceding complete breakdown of ion homeostasis is one major factor leading to cell depolarization. The massive Na+ influx coinciding with AD, however, may be mainly via non-selective cation channels or/and receptor-operated channels. Persistent Na+ influx deteriorates neuronal tissue integrity by favouring Ca2+ influx and edema formation. Blockade of ischemia-induced excessive Na+ influx is, therefore, a promising pharmacological approach for stroke treatment.
Janssen GmbH, Neuss, FRG.
Y
Y
Xie
K
K
Dengler
E
E
Zacharias
B
B
Wilffert
F
F
Tegtmeier
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002545:Brain Ischemia / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004569:Electroencephalography / Q000187:drug effects; D004594:Electrophysiology; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D008839:Microelectrodes; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology*
D015222:Sodium Channels; D013779:Tetrodotoxin