Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis

A large number of studies have documented abnormalities of glutamate metabolism in ALS patients or in postmortem ALS tissue. These abnormalities include altered synthetic enzymes, tissue glutamate levels, transporter proteins, and postsynaptic receptors, as well as the presence of potentially toxic agonists. As yet, there is no hypothesis effectively linking all the observations to one central defect. Furthermore, it is not clear if the various abnormalities in glutamate systems represent a primary defect or a secondary response. For example, defects of glutamate transport subtypes could reflect the primary loss of the proteins or the secondary effect of another toxic insult. Nevertheless, experimental paradigms suggest that, even if secondary, glutamate could contribute to the death of motor neurons. Therefore, interventions to minimize the toxicity of glutamate (e.g., receptor antagonists, release inhibitors, or antioxidants) could partially ameliorate the degeneration of motor neurons. This has been observed experimentally in cultured motor neurons. More importantly, a small study with riluzole suggests that glutamate-acting drugs could alter the progression of the disease. Future studies with riluzole and other glutamate-acting agents will evaluate this possibility.