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 mu M 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.