Neuroprotective strategies: voltage-gated Na+-channel down-modulation versus presynaptic glutamate release inhibition.
Insufficient ATP production relative to cellular requirements is the key factor detrimental to neurons in neurological disorders associated with deficient oxygen/glucose supply or mitochondrial dysfunction. As a large part of the energy consumed by brain cells is used to maintain the Na+ gradient across the cellular membrane, reduction of energy demand by down-modulation of voltage-gated Na+-channels is a rational strategy for neuroprotection against these conditions. Preservation of the inward Na+ gradient is likely to be also beneficial as it is an essential driving force for vital ion exchanges and transport mechanisms (e.g. Ca2+-homeostasis and cell volume regulation). From these elements, I propose that use-dependent Na+-channel blockers increase the resilience of nerve cells to the primary insult and/or subsequent deleterious events, and that reduced efflux of glutamate and other compounds is only a consequence of cellular stress attenuation. The widespread hypothesis that down-modulation of Na+-channels is neuroprotective primarily through reduction of presynaptic glutamate release conflicts with strong experimental evidence.
Obrenovitch
T P
TP
Postgraduate Studies in Pharmacology, School of Pharmacy, University of Bradford, UK.
D000818:Animals; D015536:Down-Regulation / Q000502:physiology*; D004594:Electrophysiology; D018698:Glutamic Acid / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D017729:Presynaptic Terminals / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*
D015222:Sodium Channels; D018698:Glutamic Acid