CommentaryHyperexcitability, persistent Na+ conductances and neurodegeneration in amyotrophic lateral sclerosis
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Hyperexcitability and persistent Na+ conductances in ALS
In addition to the hypothesized effects on glutamate release, riluzole is known to inhibit neuronal voltage-gated persistent Na+ channels. Of particular relevance to such a mechanism of action, the findings from in vitro studies have suggested that the presynaptic decrease in glutamate concentration that follows institution of riluzole therapy is linked to reduction in persistent Na+ conductances. Riluzole has been demonstrated to block persistent Na+ channels (Urbani and Belluzzi, 2000) and
Mechanisms of neurodegeneration in familial ALS
Although most cases of ALS are sporadic, approximately 10% of ALS cases are familial, whereby two or more family members are clinically affected. Inheritance of familial ALS (FALS) is usually autosomal dominant, although autosomal recessive pedigrees have also been described (Pasinelli and Brown, 2006). Current understanding is that SOD-1 mutations result in a toxic gain of function (Andersen, 2006, Kiernan, 2007). Support for this hypothesis is provided by transgenic mouse models that
Glutamate-mediated excitotoxicity
Over the past decade, studies have suggested a potential role for glutamate excitotoxicity in the pathogenesis of ALS. Glutamate is the major excitatory neurotransmitter released from presynpatic nerve terminals, with subsequent diffusion across the synaptic cleft and activation of specific postsynaptic receptors, particularly the ionotropic N-methyl-d-aspartate receptors (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors (Heath and Shaw, 2002). The excitatory
A dying forward hypothesis to ALS
Although many details of the molecular mechanisms by which glutamate exerts toxicity are yet to be clarified, several pathways have been defined. Initially, influx of Na+, Cl− and water may induce acute neuronal swelling, with subsequent entry of Ca2+ ions through NMDA and AMPA receptors and activation of Ca2+-dependent enzymatic pathways mediating neuronal death (Cox and Kirby, 2007). Glutamate excitotoxicity may also result in production of free radicals that can further damage the
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