ziconotide and Hypoxia

Neuroprotection by antagonists of both L-type and N-type calcium channels occurs in in vivo models of ischemia. The site of action of calcium channel antagonists is unclear, however, and it is likely that a combination of vascular and direct neuronal actions occurs. We have investigated the effects of blocking neuronal calcium channels using an organotypic hippocampal-slice model of ischemia.. Organotypic hippocampal-slice cultures prepared from 10-day-old rats were maintained in vitro for 14 days. Cultures were exposed to either 3 hours of oxygen deprivation (hypoxia) or 1 hour of combined oxygen and glucose deprivation (ischemia). Neuronal damage was quantified after 24 hours by propidium iodide fluorescence.. Three hours of anoxia produced damage exclusively in CAT pyramidal cells. This damage was prevented by preincubation with omega conotoxin MVIIA, a selective N-type calcium channel blocker, and omega conotoxin MVIIC, which blocks N-type and other presynaptic neuronal calcium channels. The dihydropyridine nifedipine and the mixed calcium channel blocker SB201823-A were not protective. Furthermore, if addition of conotoxin MVIIA was delayed until after the hypoxic episode, a dose-dependent neuroprotective effect was observed, with an IC50 of 50 nmol/L. In contrast to hypoxia, none of the compounds was neuroprotective in the model of oxygen-glucose deprivation, although it was determined that extracellular calcium was essential for the generation of ischemic damage.. These studies present clear evidence that neuroprotection by selective N-type calcium channel antagonists is mediated directly through neuronal calcium channels. In contrast, the neuroprotective effects of dihydropyridines may be mediated through vascular calcium channels or indirectly through actions in other brain regions.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Cells, Cultured; Dose-Response Relationship, Drug; Hippocampus; Hypoxia; Neuroprotective Agents; omega-Conotoxins; Peptides; Rats; Rats, Wistar; Time Factors