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.