title: Degeneration of spinal motor neurons by chronic AMPA-induced excitotoxicity in vivo and protection by energy substrates.
abstract: BACKGROUND
  Several data suggest that excitotoxicity due to excessive glutamatergic neurotransmission may be an important factor in the mechanisms of motor neuron (MN) death occurring in amyotrophic lateral sclerosis (ALS). We have previously shown that the overactivation of the Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptor type, through the continuous infusion of AMPA in the lumbar spinal cord of adult rats during several days, results in progressive rear limb paralysis and bilateral MN degeneration. Because it has been shown that energy failure and oxidative stress are involved in MN degeneration, in both ALS and experimental models of spinal MN degeneration, including excitotoxicity, in this work we tested the protective effect of the energy substrates pyruvate and β-hydroxybutyrate (βHB) and the antioxidants glutathione ethyl ester (GEE) and ascorbate in this chronic AMPA-induced neurodegeneration.
  
  
  RESULTS
  AMPA infusion induced remarkable progressive motor deficits, assessed by two motor tasks, that by day seven reach bilateral rear limb paralysis. These effects correlate with the death of >80% of lumbar spinal MNs in the infused and the neighbor spinal cord segments, as well as with notable astrogliosis in the ventral horns, detected by glial fibrillary acidic protein immunohistochemistry. Co-infusion with pyruvate or βHB notably prevented the motor deficits and paralysis, decreased MN loss to <25% and completely prevented the induction of astrogliosis. In contrast, the antioxidants tested were ineffective regarding all parameters analyzed.
  
  
  CONCLUSIONS
  Chronic progressive excitotoxicity due to AMPA receptors overactivation results in MN death and astrogliosis, with consequent motor deficits and paralysis. Because of the notable protection against these effects exerted by pyruvate and βHB, which are well established mitochondrial energy substrates, we conclude that deficits in mitochondrial energy metabolism are an important factor in the mechanisms of this slowly developed excitotoxic MN death, while the lack of protective effect of the antioxidants indicates that oxidative stress seems to be less significant factor. Because excitotoxicity may be involved in MN degeneration in ALS, these findings suggest possible preventive or therapeutic strategies for the disease.
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510, México DF, México. cnetza@email.ifc.unam.mx.
authors.forename: Citlalli
authors.initials: C
authors.lastname: Netzahualcoyotzi
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510, México DF, México. rtapia@ifc.unam.mx.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Tapia
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D005121:Extremities / Q000503:physiopathology; D005911:Gliosis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006885:Hydroxybutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000066829:Neuroprotection / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D010243:Paralysis / Q000139:chemically induced / Q000188:drug therapy; D019289:Pyruvic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000503:physiopathology; D016896:Treatment Outcome; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D006885:Hydroxybutyrates; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C042431:S-ethyl glutathione; D019289:Pyruvic Acid; D005978:Glutathione; D001205:Ascorbic Acid