Glutamate excitotoxicity is involved in motor dysfunctions and paralysis following infection by a human respiratory coronavirus
Bibliographic record
Abstract
Human coronaviruses (HCoV) are respiratory pathogens. We \nhave reported that strain HCoV-OC43 can infect human neuronal and glial cells, activate neuroinflammatory and neurodegenerative mechanisms, thus possibly be involved in \nneurological disease of unknown etiology, such as multiple \nsclerosis (MS). Using an animal model, we reported that a viral \npersistence-associated point mutation in the viral spike S glycoprotein (Y241H) modified neuropathology from encephalitis \nto MS-related hind-limb paralysis. Viral CNS infections may \ninduce excitotoxicity, a pathological process by which neurons \nare damaged and die following an excessive stimulation by the \nglutamate neurotransmitter on its specific ionotropic receptors \n(AMPAr and NMDAr). We have previously shown that the \nparalytic disease induced by the HCoV-OC43 S mutant \ninvolves (AMPAr)-mediated glutamate excitotoxicity. \nGiven 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 \nantagonists. Memantine is one such molecule: it modulates \nglutamate excitotoxicity and is widely used for treatment of \nhuman neurological disorders such as MS. We now show that a \nlow dose of memantine (1 μg/g body weight) improved clinical \nscores related to paralytic disease in mice infected by the \nHCoV-OC43 S mutant, without affecting viral replication. \nHowever, a 10-fold higher dose attenuated both the clinical \nscores, related to paralysis and motor dysfunctions, and mortality rates. Memantine attenuated virus replication in a dosedependent manner in cell culture, compared to dizocilpine \n(MK-801), another NMDAr antagonist, which neither affected \nvirus replication nor reduced mortality rates. Studies are currently underway to investigate the mechanisms underlying such \ndose-dependent neuroprotective and antiviral activities of \nmemantine. (Supported by operating grant MT-9203 from Canadian Institutes of Health Research (CIHR) to Pierre J. Talbot, \nwho is the holder of the Tier 1 (Senior) Canada Research Chair \nin Neuroimmunovirology award. Elodie Brison acknowledges \na doctoral studentship from the MS Society of Canada).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".