GLUTAMATE RELEASE INHIBITORS - A CRITICAL-ASSESSMENT OF THEIR ACTION MECHANISM

A number of important experimental data do not support the widespread hypothesis that Na+-channels block is cerebroprotective, essentially b ecause it reduces presynaptic glutamate release: (i) the inhibition of exocytosis by these compounds is not specific to glutamate; (ii) aspa rtate efflux produced by various stimuli was also reduced, but asparta te cannot be released by exocytosis because it is not concentrated wit hin presynaptic vesicles; and (iii) glutamate accumulated extracellula rly during ischaemic or traumatic insult to the CNS is mainly of cytos olic origin. As an alternative, we propose that use-dependent Na+-chan nel blockers enhance the resistance of nerve cells to insults, primari ly by decreasing their energy demand, and that reduced efflux of gluta mate and other compounds is a consequence of attenuated cellular stres s.