Abstract
Posthypoxic myoclonus and seizures precipitate as secondary neurological consequences in ischemic/hypoxic insults of the central nervous system. Neuronal hyperexcitation may be due to excessive activation of glutamatergic neurotransmission, an effect that has been shown to follow ischemic/hypoxic events. Therefore, riluzole, an anticonvulsant that inhibits the release of glutamate by stabilizing the inactivated state of activated voltage-sensitive sodium channels, was tested for its antimyoclonic and neuroprotective properties in the cardiac arrest-induced animal model of posthypoxic myoclonus. Riluzole (4–12 mg/kg i.p.) dose-dependently attenuated the audiogenic seizures and action myoclonus seen in this animal model. Histological examination using Nissl staining and the novel Fluoro-Jade histochemistry in cardiac-arrested animals showed an extensive neuronal degeneration in the hippocampus and cerebellum. Riluzole treatment almost completely prevented the neuronal degeneration in these brain areas. The neuroprotective effect was more pronounced in hippocampal pyramidal neurons and cerebellar Purkinje cells. These effects were seen at therapeutically relevant doses of riluzole, and the animals tolerated the treatment well. These findings indicate that the pathogenesis of posthypoxic myoclonus and seizure may involve excessive activation of glutamate neurotransmission, and that riluzole may serve as an effective pharmacological agent with neuroprotective potential for the treatment of neurological conditions associated with cardiac arrest in humans.
Footnotes
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Send reprint requests to: Anumantha Kanthasamy, Ph.D., Parkinson’s and Movement Disorders Institute, Long Beach Memorial Medical Center Research Building, 2801 Atlantic Avenue, P.O. Box 1428, Long Beach, CA 90801-1428. E-mail: akanthas{at}uci.edu
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↵1 This work was supported by the Myoclonus Research Foundation and clinical funds from the Parkinson’s and Movement Disorders Institute. The histology work was made possible, in part, through access to the Optical Biology Shared Resource of the Cancer Center Support Grant CA-62203 at the University of California, Irvine. Support from the National Institutes of Health-Society for Advancement of Chicanos and Native Americans in Science Biomedical Research for undergraduate students through the University of California, Irvine is gratefully acknowledged. This work was presented in part at the 27th Annual Meeting of the Society for Neuroscience, New Orleans, LA, October 1997.
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↵2 Current address: Department of Neurology, College of Medicine, University of California Irvine, Irvine, CA 92697.
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↵3 Current address: Department of Community & Environmental Medicine, College of Medicine, University of California Irvine, Irvine, CA 92697.
- Abbreviations:
- CNS
- central nervous system
- NMDA
- N-methyl-d-aspartate
- Received July 13, 1998.
- Accepted October 7, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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