Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection

doi:10.1073/pnas.0712390105

Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205

Contributed by Diane E. Griffin, January 8, 2008 (received for review December 15, 2007)

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.

Footnotes

^§To whom correspondence should be addressed at:
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E5132, Baltimore, MD 21205.
E-mail: dgriffin{at}jhsph.edu
Author contributions: I.P.G. and D.E.G. designed research; I.P.G., E.-Y.L., N.P., and B.N. performed research; I.P.G. and D.E.G. analyzed data; and I.P.G. and D.E.G. wrote the paper.
↵*Present address: Department of Anatomy, College of Medicine, Chungbuk National University, 12 Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, South Korea.
↵ ^†Present address: Department of Microbiology and Parasitology, School of Molecular and Microbial Sciences, University of Queensland, St. Lucia, Brisbane 4072, Australia.
↵ ^‡Present address: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
The authors declare no conflict of interest.