AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo.

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: Juan Carlos Corona, Ricardo Tapia
• Journal: Journal of neurochemistry (J Neurochem) Vol. 89 Issue 4 Pg. 988-97 (May 2004) ISSN: 0022-3042 [Print] England
• PMID: 15140197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Excitatory Amino Acid Agonists
• Excitatory Amino Acid Antagonists
• Potassium Channel Blockers
• Receptors, AMPA
• Glutamic Acid
• N-Methylaspartate
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
• Potassium
• Kainic Acid

Topics

• Animals
• Drug Administration Routes
• Excitatory Amino Acid Agonists (administration & dosage)
• Excitatory Amino Acid Antagonists (pharmacology)
• Extracellular Fluid (metabolism)
• Glutamic Acid (metabolism)
• Hindlimb (physiopathology)
• Kainic Acid (pharmacology)
• Lumbosacral Region
• Male
• Microdialysis
• Motor Neurons (drug effects, metabolism, pathology)
• N-Methylaspartate (pharmacology)
• Paralysis (chemically induced, pathology, physiopathology)
• Perfusion
• Potassium (pharmacology)
• Potassium Channel Blockers (pharmacology)
• Rats
• Receptors, AMPA (drug effects, metabolism)
• Spinal Cord (drug effects, metabolism, pathology)
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (administration & dosage, toxicity)