NMDA receptor antagonists mitigate COVID-19-induced neuroinflammation and improve survival in a mouse model

Emily R. Prantzalos, Jane P. Chesser, Judy Songrady Logan, Kristen A. McLaurin, Charles D. Anderson, Jon D. Gabbard, William E. Severson, Kenneth E. Palmer, Bobbi Jo Mullins, Linda Dwoskin, Jill Ortinski

Research output: Contribution to journalArticlepeer-review

Abstract

The virus known to cause COVID-19, SARS-CoV-2, exhibits severe and complex neurological symptoms. These effects may be attributed to a virus-induced neuroinflammatory environment, warranting exploration of the respiratory centers of the brain, namely the pons and medulla, specifically in relation to neuroinflammation, demyelination, and neuronal death in response to COVID-19. Interestingly, older adults with neurological dysfunction maintained on N-methyl-d-aspartate receptor (NMDAR) antagonists, such as memantine, had reduced incidence and severity of COVID-19. Thus, the present study aimed to evaluate (1) the neuroinflammatory response to COVID-19 in the respiratory centers of the brain, and (2) to assess the extent to which NMDAR antagonists offer neuroprotective measures in the context of COVID-19. In a susceptible mouse model, animals inoculated with SARS-CoV-2 were pre-treated with either memantine or an alternative NMDAR antagonist, ifenprodil. Inoculated animals had poor survival and showed signs of neuroinflammation, evidenced by a reduction in morphological structure, demyelination, and changes in astrocyte and microglial expression in the pons and medulla. Mice pre-treated with memantine showed improved survival when challenged with COVID-19 and a reduction in virus-induced neuroinflammatory impairments. Our findings support the further investigation of memantine for the prevention of COVID-19 induced neuroinflammation and resultant neurological symptoms and shed light on the possible protective mechanism of memantine in the elderly maintained on NMDAR antagonists.

Original languageEnglish
Article number19603
JournalScientific Reports
Volume15
Issue number1
DOIs
StatePublished - Dec 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

The funding statement provided by National Institute on Drug Abuse, F31-DA-057812, American Foundation for Pharmaceutical Education, National Center for Advancing Translational Sciences (Grant No. UL1TR001998).

FundersFunder number
American Foundation for Pharmaceutical Education
Author National Institute on Drug Abuse DA031791 Mark J Ferris National Institute on Drug Abuse DA006634 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA026117 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA028162 Elizabeth G Pitts National Institute of General Medical Sciences GM102773 Elizabeth G Pitts Peter McManus Charitable Trust Mark J Ferris National Institute on Drug AbuseF31-DA-057812
Author National Institute on Drug Abuse DA031791 Mark J Ferris National Institute on Drug Abuse DA006634 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA026117 Mark J Ferris National Institute on Alcohol Abuse and Alcoholism AA028162 Elizabeth G Pitts National Institute of General Medical Sciences GM102773 Elizabeth G Pitts Peter McManus Charitable Trust Mark J Ferris National Institute on Drug Abuse
National Center for Advancing Translational Sciences (NCATS)UL1TR001998
National Center for Advancing Translational Sciences (NCATS)

    ASJC Scopus subject areas

    • General

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