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 because it reduces presynaptic glutamate release: (i) the inhibition of exocytosis by these compounds is not specific to glutamate; (ii) aspartate efflux produced by various stimuli was also reduced, but aspartate cannot be released by exocytosis because it is not concentrated within presynaptic vesicles; and (iii) glutamate accumulated extracellularly during ischaemic or traumatic insult to the CNS is mainly of cytosolic origin. As an alternative, we propose that use-dependent Na(+)-channel blockers enhance the resistance of nerve cells to insults, primarily by decreasing their energy demand, and that reduced efflux of glutamate and other compounds is a consequence of attenuated cellular stress.
Obrenovitch
T P
TP
Department of Neurochemistry, Institute of Neurology, London, United Kingdom.
Urenjak
J
J
D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005089:Exocytosis / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D015640:Ion Channel Gating; D018696:Neuroprotective Agents / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000187:drug effects*; D026941:Sodium Channel Blockers
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; D026941:Sodium Channel Blockers; D018698:Glutamic Acid