Prophylactic clemastine treatment improves influenza A virus-induced cognitive dysfunction in mice

Abstract

Respiratory infection by influenza A virus (IAV) is known to cause systemic inflammation, neuroinflammation, and cognitive impairment. We previously found that experimental infection with IAV affected oligodendrocyte homeostasis, which was associated with altered expression of genes involved in myelin maintenance as well as the lipidome. In this study, we sought to determine if clemastine, an antihistamine with myelin promoting properties, could reverse the effects of IAV on oligodendrocyte (OL) specific genes, as well as mitigate infection-induced cognitive impairment. Male and female C57BL/6J mice were randomized into experimental groups based on clemastine treatment, infection, and sex. Treatment with vehicle or clemastine (10 mg/kg/d) commenced seven days prior to inoculation with either saline or IAV and continued throughout the experiment. Body weight was measured throughout the infection. Spatial learning and memory were assessed by Morris water maze. Sickness behavior was assessed by measuring burrowing response. Immune cell responses were determined by flow cytometry, RT-qPCR, antigen recall assays and ELISA, and viral load assessed by RT-qPCR. Hippocampal levels of neuroinflammatory (Tnf, Cdkn1a) and myelin (Plp1, Mag, Ugt8a) genes were determined by RT-qPCR. Mice infected with IAV developed weight loss, impaired cognitive flexibility, reduced burrowing behavior, altered lung immune cell infiltration, increased circulating anti-viral IgM and IgG levels and increased T cell responses to IAV epitopes. Infection increased hippocampal levels of genes associated with neuroinflammation and decreased levels of genes involved in myelination. Clemastine treatment resulted in earlier recovery of weight loss in males and increased IgM levels for both sexes, but neither affected expression levels of Tnf or Cdkn1a, nor rescued changes to oligodendrocyte genes. However, treatment mitigated infection-induced neurocognitive impairment.