Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection
Open Access
- 4 March 2008
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (9), 3575-3580
- https://doi.org/10.1073/pnas.0712390105
Abstract
Neuronal cell death during fatal acute viral encephalomyelitis can result from damage caused by virus replication, glutamate excitotoxicity, and the immune response. A neurovirulent strain of the alphavirus Sindbis virus (NSV) causes fatal encephalomyelitis associated with motor neuron death in adult C57BL/6 mice that can be prevented by treatment with the prototypic noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor antagonist GYKI 52466 [Nargi-Aizenman J, et al. (2004) Ann Neurol 55:541–549]. To determine the mechanism of protection, NSV-infected mice were treated with 7-acetyl-5-(4-aminophenyl)-8(R)-methyl-8,9-dihydro-7H-1,3-dioxolo-(4,5-h)-benzodiazepine (talampanel), a potent, orally available member of the 2,3 benzodiazepine class of noncompetitive AMPA glutamate receptor antagonists. Talampanel-treated mice were protected from NSV-induced paralysis and death. Examination of the brain during infection showed significantly less mononuclear cell infiltration and no increase in astrocyte expression of glial fibrillary acidic protein in treated mice compared with untreated mice. Lack of CNS inflammation was attributable to failure of treated mice to induce activation and proliferation of lymphocytes in secondary lymphoid tissue in response to infection. Antibody responses to NSV were also suppressed by talampanel treatment, and virus clearance was delayed. These studies reveal a previously unrecognized effect of AMPA receptor antagonists on the immune response and suggest that prevention of immune-mediated damage, in addition to inhibition of excitotoxicity, is a mechanism by which these drugs protect from death of motor neurons caused by viral infection.Keywords
This publication has 72 references indexed in Scilit:
- Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicityProceedings of the National Academy of Sciences, 2007
- Neuroprotective Interventions Targeting Detrimental Host Immune Responses Protect Mice From Fatal Alphavirus EncephalitisJournal of Neuropathology and Experimental Neurology, 2007
- The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitisExperimental Neurology, 2007
- Induction of IP-10 (CXCL10) in astrocytes following Japanese encephalitisNeuroscience Letters, 2007
- Rodent lymphocytes express functionally active glutamate receptorsBiochemical and Biophysical Research Communications, 2004
- AlphavirusesPublished by Wiley ,2002
- Interferon-γ-Mediated Site-Specific Clearance of Alphavirus from CNS NeuronsScience, 2001
- Immunocytochemical identification and quantitation of the mononuclear cells in the cerebrospinal fluid, meninges, and brain during acute viral meningoencephalitis.The Journal of Experimental Medicine, 1984
- SPECIFICITY OF THE INFLAMMATORY RESPONSE IN VIRAL ENCEPHALITISThe Journal of Experimental Medicine, 1972
- Age-dependent Resistance to Viral Encephalitis: Studies of Infections Due to Sindbis Virus in MiceThe Journal of Infectious Diseases, 1972