Glutamate receptor antagonists protect from virus-induced neural degeneration.
Neuronal damage during acute viral encephalomyelitis can result directly from virus infection or indirectly from the host immune response to infection. In neurodegenerative diseases and stroke, neuronal death also can result from excess release of excitatory amino acid neurotransmitters, such as glutamate. To determine the role of glutamate excitotoxicity in fatal alphavirus-induced paralytic encephalomyelitis, we treated mice infected with neuroadapted Sindbis virus (NSV) with antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtypes of glutamate receptors. Both apoptotic and necrotic neurons in the hippocampus were decreased in animals treated with MK-801, an NMDA receptor antagonist, or GYKI-52466, an AMPA receptor antagonist. However, only AMPA receptor blockade prevented damage to spinal cord motor neurons and protected mice from paralysis and death due to NSV infection. Protection was not caused by altered virus replication because treatment did not affect virus distribution and actually delayed virus clearance. These results provide evidence that NSV infection activates neurotoxic pathways that result in aberrant glutamate receptor stimulation and neuronal damage. Furthermore, AMPA receptor-mediated motor neuron death is an important contributor to paralysis and mortality in acute alphavirus-induced encephalomyelitis.
Nargi-Aizenman
Jennifer L
JL
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Havert
Michael B
MB
Zhang
Ming
M
Irani
David N
DN
Rothstein
Jeffrey D
JD
Griffin
Diane E
DE
D018354:Alphavirus Infections / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000821:virology; D018792:Encephalitis, Viral / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D017470:Receptors, Glutamate / Q000502:physiology*; D012845:Sindbis Virus / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000821:virology
D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate