Successful protection by amantadine hydrochloride against lethal encephalitis caused by a highly neurovirulent recombinant influenza A virus in mice.
A mouse model system for a lethal encephalitis due to influenza has been established by stereotaxic microinjection with the recombinant R404BP strain of influenza A virus into the olfactory bulb of C57BL/6 mice. The virus infection spread selectively to neurons in nuclei of the broad areas of the brain parenchyma that have anatomical connections to the olfactory bulb, leading to apoptotic neurodegeneration. The inflammatory reaction at the extended stage of viral infection involved the vascular structures affected by induction of inducible nitric oxide synthase and protein nitration; those were related to the etiology of fatal brain edema. The intraperitoneal administration of amantadine inhibited the viral growth in the brain and saved mice from the lethal encephalitis. The severity of neuronal loss paralleled the time lag between the virus challenge and the start of amantadine treatment. Thus, early pharmacological intervention is essential to minimize neurological deficits due to influenza virus-induced neurodegeneration.
Mori
Isamu
I
Department of Microbiology, Fukui Medical University School of Medicine, Fukui, Japan.
Liu
Beixing
B
Hossain
Md Jaber
MJ
Takakuwa
Hiroki
H
Daikoku
Tohru
T
Nishiyama
Yukihiro
Y
Naiki
Hironobu
H
Matsumoto
Kazuo
K
Yokochi
Takashi
T
Kimura
Yoshinobu
Y
D000547:Amantadine / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D018792:Encephalitis, Viral / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D005260:Female; D009980:Influenza A virus / Q000235:genetics / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D011995:Recombination, Genetic; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis
D000998:Antiviral Agents; C002744:3-nitrotyrosine; D014443:Tyrosine; D000547:Amantadine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse