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AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo.
J Neurochem. 2004 May; 89(4):988-97.JN

Abstract

The mechanisms of motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS) are unknown, but glutamate-mediated excitotoxicity may be involved. To examine directly this idea in vivo, we have used microdialysis in the rat lumbar spinal cord and showed that four- to fivefold increases in the concentration of endogenous extracellular glutamate during at least 1 h, by perfusion with the glutamate transport inhibitor L-2,4-trans-pyrrolidine-dicarboxylate, elicited no motor alterations or MN damage. Stimulation of glutamate release with 4-aminopyridine induced transitory ipsilateral hindlimb muscular twitches but no MN damage. In contrast, perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) did not modify glutamate levels but produced intense muscular spasms, followed by ipsilateral permanent hindlimb paralysis and a remarkable loss of MNs. These effects of AMPA were prevented by co-perfusion with the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline. Perfusion with NMDA or kainate produced no motor effects or MN damage. Thus, the elevation of endogenous extracellular glutamate in vivo due to blockade of its transport is innocuous for spinal MNs. Because this resistance is observed under the same experimental conditions in which MNs are highly vulnerable to AMPA, these results indicate that excitotoxicity due to this mechanism might not be an important factor in the pathogenesis of ALS.

Authors+Show Affiliations

Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México, D. F., México.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15140197

Citation

Corona, Juan Carlos, and Ricardo Tapia. "AMPA Receptor Activation, but Not the Accumulation of Endogenous Extracellular Glutamate, Induces Paralysis and Motor Neuron Death in Rat Spinal Cord in Vivo." Journal of Neurochemistry, vol. 89, no. 4, 2004, pp. 988-97.
Corona JC, Tapia R. AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo. J Neurochem. 2004;89(4):988-97.
Corona, J. C., & Tapia, R. (2004). AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo. Journal of Neurochemistry, 89(4), 988-97.
Corona JC, Tapia R. AMPA Receptor Activation, but Not the Accumulation of Endogenous Extracellular Glutamate, Induces Paralysis and Motor Neuron Death in Rat Spinal Cord in Vivo. J Neurochem. 2004;89(4):988-97. PubMed PMID: 15140197.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo. AU - Corona,Juan Carlos, AU - Tapia,Ricardo, PY - 2004/5/14/pubmed PY - 2004/6/5/medline PY - 2004/5/14/entrez SP - 988 EP - 97 JF - Journal of neurochemistry JO - J Neurochem VL - 89 IS - 4 N2 - The mechanisms of motor neuron (MN) degeneration in amyotrophic lateral sclerosis (ALS) are unknown, but glutamate-mediated excitotoxicity may be involved. To examine directly this idea in vivo, we have used microdialysis in the rat lumbar spinal cord and showed that four- to fivefold increases in the concentration of endogenous extracellular glutamate during at least 1 h, by perfusion with the glutamate transport inhibitor L-2,4-trans-pyrrolidine-dicarboxylate, elicited no motor alterations or MN damage. Stimulation of glutamate release with 4-aminopyridine induced transitory ipsilateral hindlimb muscular twitches but no MN damage. In contrast, perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) did not modify glutamate levels but produced intense muscular spasms, followed by ipsilateral permanent hindlimb paralysis and a remarkable loss of MNs. These effects of AMPA were prevented by co-perfusion with the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline. Perfusion with NMDA or kainate produced no motor effects or MN damage. Thus, the elevation of endogenous extracellular glutamate in vivo due to blockade of its transport is innocuous for spinal MNs. Because this resistance is observed under the same experimental conditions in which MNs are highly vulnerable to AMPA, these results indicate that excitotoxicity due to this mechanism might not be an important factor in the pathogenesis of ALS. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/15140197/AMPA_receptor_activation_but_not_the_accumulation_of_endogenous_extracellular_glutamate_induces_paralysis_and_motor_neuron_death_in_rat_spinal_cord_in_vivo_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=2004&volume=89&issue=4&spage=988 DB - PRIME DP - Unbound Medicine ER -