Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis.
Two forms of amyotrophic lateral sclerosis (ALS) are known, the familial (FALS), due in part to mutations in superoxide dismutase 1 (SOD1), and the sporadic (SALS), which accounts for > 90% of all cases. The cause of SALS is not known, but excitotoxicity due to overactivation of glutamate receptors may mediate the motor neuron degeneration in the spinal cord, which is the hallmark of this disease. Overactivation of calcium-permeable alpha-amino-3-hydroxy-5-isoxazole propionate receptors lacking the subunit glutamate receptor 2, leading to an increase in calcium cytoplasmic concentration, seems to play an important role in the mechanism of neuronal death. The knowledge of this mechanism, in addition to other factors, provides several possible targets for therapeutic strategies that are reviewed in this article. Some of these strategies have proven to be partially effective in both human mutant superoxide dismutase 1 transgenic rodents (FALS model) and the few existing in vivo models of spinal motor neurodegeneration induced by excitotoxicity (SALS models), although observable benefits are still to be shown in clinical trials.
Corona
Juan C
JC
Universidad Nacional Autönoma de México, Departamento de Neurociencias, Instituto de Fisiología Celular, AP 70-253, 04510-México, D.F., México.
Tovar-y-Romo
Luis B
LB
Tapia
Ricardo
R
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D018698:Glutamic Acid / Q000502:physiology*; D006801:Humans; D009474:Neurons; D018091:Receptors, AMPA / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D018698:Glutamic Acid; D002118:Calcium