Brison, Élodie; Jacomy, Hélène; Desforges, Marc et Talbot, Pierre J. 
ORCID: https://orcid.org/0000-0003-4203-7744
(2012).
Glutamate excitotoxicity is involved in motor dysfunctions and paralysis following infection by a human respiratory coronavirus
In: 11th International Symposium on NeuroVirology (ISNV) Meeting, May 29-June 2, 2012, New York.
Résumé
Human coronaviruses (HCoV) are respiratory pathogens. We
have reported that strain HCoV-OC43 can infect human neuronal and glial cells, activate neuroinflammatory and neurodegenerative mechanisms, thus possibly be involved in
neurological disease of unknown etiology, such as multiple
sclerosis (MS). Using an animal model, we reported that a viral
persistence-associated point mutation in the viral spike S glycoprotein (Y241H) modified neuropathology from encephalitis
to MS-related hind-limb paralysis. Viral CNS infections may
induce excitotoxicity, a pathological process by which neurons
are damaged and die following an excessive stimulation by the
glutamate neurotransmitter on its specific ionotropic receptors
(AMPAr and NMDAr). We have previously shown that the
paralytic disease induced by the HCoV-OC43 S mutant
involves (AMPAr)-mediated glutamate excitotoxicity.
Given that overactivation of the N-methyl-D-aspartic acid receptor (NMDAr) may also lead to excitotoxicity, pharmacological research has focused on the development of NMDAr
antagonists. Memantine is one such molecule: it modulates
glutamate excitotoxicity and is widely used for treatment of
human neurological disorders such as MS. We now show that a
low dose of memantine (1 μg/g body weight) improved clinical
scores related to paralytic disease in mice infected by the
HCoV-OC43 S mutant, without affecting viral replication.
However, a 10-fold higher dose attenuated both the clinical
scores, related to paralysis and motor dysfunctions, and mortality rates. Memantine attenuated virus replication in a dosedependent manner in cell culture, compared to dizocilpine
(MK-801), another NMDAr antagonist, which neither affected
virus replication nor reduced mortality rates. Studies are currently underway to investigate the mechanisms underlying such
dose-dependent neuroprotective and antiviral activities of
memantine. (Supported by operating grant MT-9203 from Canadian Institutes of Health Research (CIHR) to Pierre J. Talbot,
who is the holder of the Tier 1 (Senior) Canada Research Chair
in Neuroimmunovirology award. Elodie Brison acknowledges
a doctoral studentship from the MS Society of Canada).
| Type de document: | Document issu d'une conférence ou d'un atelier |
|---|---|
| Informations complémentaires: | Affiche scientifique P35 Journal of Neurovirology 18(suppl.1):17-18 |
| Mots-clés libres: | - |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 28 janv. 2024 14:55 |
| Dernière modification: | 28 janv. 2024 14:55 |
| URI: | https://espace.inrs.ca/id/eprint/14118 |
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