Riluzole, neuroprotection and amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease of the human motor system. Aetiological mechanisms implicated in the development of ALS have been linked to the glutamatergic neurotransmitter system, with destruction of motor neurons triggered through excessive activation of glutamate receptors at the synaptic cleft. This 'excitotoxicity' theory of ALS gave rise to the development of therapeutic approaches and ultimately clinical trials involving riluzole, initially thought to act solely as an inhibitor of glutamate release. Subsequent effects of riluzole have been postulated to include indirect antagonism of glutamate receptors, in addition to inactivation of neuronal voltage-gated Na+ channels. Riluzole remains the only disease-modifying therapy available to patients with ALS. Despite having been clinically available since the mid-1990 s, the in vivo pharmacological targets of riluzole have been poorly defined. An improved understanding concerning the potential neuroprotective mechanisms of riluzole may unearth pathophysiological processes that mediate neurodegeneration in ALS. The present review summarises the known chemical and pharmacological properties of riluzole. The failure of other putative neuroprotective therapies to demonstrate positive treatment outcomes in this intractable disease will be reviewed. Finally, the hypothesis that Na+ conductances may be involved in the processes of neuronal and axonal degeneration in ALS will be explored.
Cheah
B C
BC
Prince of Wales Medical Research Institute, Barker Street, Randwick, NSW 2031, Australia.
Vucic
S
S
Krishnan
A V
AV
Kiernan
M C
MC
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D002986:Clinical Trials as Topic; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D019782:Riluzole / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D019782:Riluzole