Alphavirus Encephalomyelitis: Mechanisms and Approaches to Prevention of Neuronal Damage

Research output: Contribution to journalArticle

Abstract

Mosquito-borne viruses are important causes of death and long-term neurologic disability due to encephalomyelitis. Studies of mice infected with the alphavirus Sindbis virus have shown that outcome is dependent on the age and genetic background of the mouse and virulence of the infecting virus. Age-dependent susceptibility reflects the acquisition by neurons of resistance to virus replication and virus-induced cell death with maturation. In mature mice, the populations of neurons most susceptible to infection are in the hippocampus and anterior horn of the spinal cord. Hippocampal infection leads to long-term memory deficits in mice that survive, while motor neuron infection can lead to paralysis and death. Neuronal death is immune-mediated, rather than a direct consequence of virus infection, and associated with entry and differentiation of pathogenic T helper 17 cells in the nervous system. To modulate glutamate excitotoxicity, mice were treated with an N-methyl-D-aspartate receptor antagonist, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists or a glutamine antagonist. The N-methyl-D-aspartate receptor antagonist MK-801 protected hippocampal neurons but not motor neurons, and mice still became paralyzed and died. α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists GYKI-52466 and talampanel protected both hippocampal and motor neurons and prevented paralysis and death. Glutamine antagonist 6-diazo-5-l-norleucine protected hippocampal neurons and improved memory generation in mice surviving infection with an avirulent virus. Surprisingly, in all cases protection was associated with inhibition of the antiviral immune response, reduced entry of inflammatory cells into the central nervous system, and delayed virus clearance, emphasizing the importance of treatment approaches that include prevention of immunopathologic damage.

Original languageEnglish (US)
Pages (from-to)1-6
Number of pages6
JournalNeurotherapeutics
DOIs
StateAccepted/In press - Apr 25 2016

Fingerprint

Alphavirus
Encephalomyelitis
Viruses
Motor Neurons
Isoxazoles
Neurons
Infection
N-Methyl-D-Aspartate Receptors
Glutamine
GYKI 53405
Paralysis
Nervous System
Norleucine
Sindbis Virus
Th17 Cells
Dizocilpine Maleate
Long-Term Memory
Memory Disorders
Virus Diseases
Virus Replication

Keywords

  • AMPA receptor antagonist
  • Glutamate excitotoxicity
  • Glutamine antagonist
  • Immunopathogenesis
  • Sindbis virus

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Clinical Neurology
  • Pharmacology

Cite this

Alphavirus Encephalomyelitis : Mechanisms and Approaches to Prevention of Neuronal Damage. / Griffin, Diane.

In: Neurotherapeutics, 25.04.2016, p. 1-6.

Research output: Contribution to journalArticle

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