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Calpain Inhibition Protects Spinal Motoneurons from the Excitotoxic Effects of AMPA In vivo

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Abstract

Microdialysis perfusion of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in rat lumbar spinal cord produces severe motoneuron damage and consequently hindlimb paralysis. Here we studied the time course of the AMPA-induced neurodegenerative changes and motor alterations, and the protective effect of leupeptin, an inhibitor of calpain, a Ca2+-activated protease. Paralysis occurs at 4–6 h after AMPA perfusion, but cresyl violet staining showed that motoneuron damage starts at about 3 h and progresses until reaching 50% neuronal loss at 6 h and 90% loss at 12 h. In contrast, choline acetyltransferase (ChAT) immunohistochemistry revealed that the enzyme is already decreased at 30 min after AMPA perfusion and practically disappears at 3 h. Microdialysis coperfusion of leupeptin with AMPA prevented the motor alterations and paralysis and remarkably reduced both the decrement in ChAT immunoreactivity and the loss of motoneurons. We conclude that an increased Ca2+ influx through Ca2+-permeable AMPA receptors activates calpain, and as a consequence ChAT content decreases earlier than other Ca2+-dependent processes, including the proteolytic activity of calpain, cause the death of motoneurons.

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Acknowledgments

This research was supported by CONACYT, México (project 60322) and DGAPA, UNAM (project IN209807). JC Corona received a fellowship from CONACYT. The authors thank Federico Jandete for help in the cresyl violet staining procedure.

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Authors and Affiliations

  1. Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510, Mexico, DF, Mexico

    Juan Carlos Corona & Ricardo Tapia

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  1. Juan Carlos Corona
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  2. Ricardo Tapia
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Correspondence to Ricardo Tapia.

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Special issue article in honor of Dr. Ricardo Tapia.

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Corona, J.C., Tapia, R. Calpain Inhibition Protects Spinal Motoneurons from the Excitotoxic Effects of AMPA In vivo. Neurochem Res 33, 1428–1434 (2008). https://doi.org/10.1007/s11064-007-9559-7

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  • DOI: https://doi.org/10.1007/s11064-007-9559-7

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