Early vitamin B12 treatment mitigates hippocampal neuroinflammation and neurodegeneration in a hamster model of long COVID

DOI record: { "DOI": "10.21203/rs.3.rs-9912983/v1", "URL": "http://dx.doi.org/10.21203/rs.3.rs-9912983/v1", "abstract": "<title>Abstract</title>\n <p>\n Background\n Cognitive impairment in long COVID is linked to hippocampal neuroinflammation and elevated CCL11, a chemokine associated with microgliosis and neuronal dysfunction. Concurrently, vitamin B12 has emerged as a potential modulator of neuroinflammatory pathways, including inhibition of\n <italic>CCL11</italic>\n transcription.\nMethods\n Adult Syrian golden hamsters were intranasally infected with SARS-CoV-2 (Omicron variant) and treated with B12 beginning three days after infection. Body weight and food intake were monitored during the acute phase. On day 15 post-infection, hippocampal transcriptomic alterations were investigated by RNA-Seq, microgliosis was assessed by Iba1 immunohistochemistry, and mature neuronal density (NeuN+) together with alpha-synuclein levels were evaluated by immunofluorescence in the CA1 and CA3 hippocampal subregions. Plasma B12 concentrations, as well as plasma and hippocampal CCL11 levels, were quantified by ELISA.\nResults\n SARS-CoV-2 infection induced weight loss and reduced food intake during the acute phase and subsequently increased hippocampal CCL11 levels, as well as transcriptomic reprogramming in the hippocampus, microgliosis, and reduction in mature neuron density compatible with neurodegenerative processes in the hippocampus. In females, activation of pathways associated with neurodegenerative processes, together with microgliosis and reduced mature neuronal density, were observed in both the CA1 and the CA3, whereas males exhibited microgliosis restricted to the CA3. Basal hippocampal CCL11 levels were higher in males, whereas infection-induced increases were more pronounced in females. B12 prevented weight loss, inappetence, and the increase in hippocampal CCL11 levels independently of sex, while attenuating transcriptomic, microglial, and neuronal alterations in a sex-dependent manner.\nConclusions\n These findings support a role for CCL11 in long COVID-associated hippocampal dysfunction and suggest that early B12 administration may mitigate neuroinflammatory and neurodegenerative sequelae, highlighting its potential as an adjuvant therapy for neurological complications of COVID-19.\n </p>", "accepted": { "date-parts": [ [ 2026, 6, 3 ] ] }, "author": [ { "affiliation": [ { "name": "Instituto René Rachou (IRR), Fundação Oswaldo Cruz (Fiocruz)" } ], "family": "Oliveira", "given": "Marina da Silva", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "first" }, { "affiliation": [ { "name": "Instituto René Rachou (IRR), Fundação Oswaldo Cruz (Fiocruz)" } ], "family": "Silva-Contigli", "given": "Leonardo", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Instituto René Rachou (IRR), Fundação Oswaldo Cruz (Fiocruz)" } ], "family": "Salim", "given": "Anna Cristina de Matos", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Instituto René Rachou (IRR), Fundação Oswaldo Cruz (Fiocruz)" } ], "family": "de Souza", "given": "Dayane Lorena Naves", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz)" } ], "family": "de Souza", "given": "Natália Satchiko Hojo", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Faculdade de Medicina da Universidade Federal de Minas Gerais (UFMG)" } ], "family": "Romano-Silva", "given": "Marco Aurélio", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" }, { "affiliation": [ { "name": "Instituto René Rachou (IRR), Fundação Oswaldo Cruz (Fiocruz)" } ], "family": "Coimbra", "given": "Roney Santos", "role": [ { "role": "author", "vocabulary": "crossref" } ], "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2026, 7, 1 ] ], "date-time": "2026-07-01T15:16:25Z", "timestamp": 1782918985000 }, "deposited": { "date-parts": [ [ 2026, 7, 1 ] ], "date-time": "2026-07-01T15:16:29Z", "timestamp": 1782918989000 }, "group-title": "In Review", "indexed": { "date-parts": [ [ 2026, 7, 1 ] ], "date-time": "2026-07-01T15:48:57Z", "timestamp": 1782920937907, "version": "3.54.5" }, "institution": [ { "name": "Research Square" } ], "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2026, 7, 1 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "unspecified", "delay-in-days": 0, "start": { "date-parts": [ [ 2026, 7, 1 ] ], "date-time": "2026-07-01T00:00:00Z", "timestamp": 1782864000000 } } ], "link": [ { "URL": "https://www.researchsquare.com/article/rs-9912983/v1", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.researchsquare.com/article/rs-9912983/v1.html", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "posted": { "date-parts": [ [ 2026, 7, 1 ] ] }, "prefix": "10.21203", "published": { "date-parts": [ [ 2026, 7, 1 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1038/s41579-022-00846-2", "article-title": "Long COVID: major findings, mechanisms and recommendations", "author": "Davis HE", "doi-asserted-by": "crossref", "first-page": "133", "issue": "3", "journal-title": "Nat Rev Microbiol", "key": "ref1", "unstructured": "Davis HE, McCorkell L, Vogel JM, Topol EJ (2023) Long COVID: major findings, mechanisms and recommendations. 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