title: Role of energy metabolic deficits and oxidative stress in excitotoxic spinal motor neuron degeneration in vivo.
abstract: MN (motor neuron) death in amyotrophic lateral sclerosis may be mediated by glutamatergic excitotoxicity. Previously, our group showed that the microdialysis perfusion of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) in the rat lumbar spinal cord induced MN death and permanent paralysis within 12 h after the experiment. Here, we studied the involvement of energy metabolic deficiencies and of oxidative stress in this MN degeneration, by testing the neuroprotective effect of various energy metabolic substrates and antioxidants. Pyruvate, lactate, β-hydroxybutyrate, α-ketobutyrate and creatine reduced MN loss by 50-65%, preserved motor function and completely prevented the paralysis. Ascorbate, glutathione and glutathione ethyl ester weakly protected against motor deficits and reduced MN death by only 30-40%. Reactive oxygen species formation and 3-nitrotyrosine immunoreactivity were studied 1.5-2 h after AMPA perfusion, during the initial MN degenerating process, and no changes were observed. We conclude that mitochondrial energy deficiency plays a crucial role in this excitotoxic spinal MN degeneration, whereas oxidative stress seems a less relevant mechanism. Interestingly, we observed a clear correlation between the alterations of motor function and the number of damaged MNs, suggesting that there is a threshold of about 50% in the number of healthy MNs necessary to preserve motor function.
authors: *División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510-México, D.F., México.
authors: Luz Diana
authors: LD
authors: Santa-Cruz
authors: *División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510-México, D.F., México.
authors: Ricardo
authors: R
authors: Tapia
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D008159:Lumbar Vertebrae; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009410:Nerve Degeneration / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010243:Paralysis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C002744:3-nitrotyrosine; D014443:Tyrosine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid