COVID‐19 Infection Enhances Susceptibility to Oxidative Stress–Induced Parkinsonism

BACKGROUND: Viral induction of neurological syndromes has been a concern since parkinsonian‐like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection with those observed after pandemic influenza, there is a question whether a similar syndrome of postencephalic parkinsonism could follow coronavirus disease 2019 infection. OBJECTIVE: The goal of this study was to determine whether prior infection with SARS‐CoV‐2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism. METHODS: K18‐hACE2 mice were infected with SARS‐CoV‐2 to induce mild‐to‐moderate disease. After 38 days of recovery, mice were administered a non‐lesion‐inducing dose of the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and euthanized 7 days later. Subsequent neuroinflammation and substantia nigra pars compacta (SNpc) dopaminergic (DA) neuron loss were determined and compared with SARS‐CoV‐2 or MPTP alone. RESULTS: K18‐hACE2 mice infected with SARS‐CoV‐2 or MPTP showed no SNpc DA neuron loss after MPTP. In mice infected and recovered from SARS‐CoV‐2 infection, MPTP induced a 23% or 19% greater loss of SNpc DA neurons than SARS‐CoV‐2 or MPTP, respectively (P < 0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in both the SNpc and striatum of the SARS‐CoV‐2 + MPTP group compared with SARS‐CoV‐2 or MPTP alone. CONCLUSIONS: Our observations have important implications for long‐term public health, given the number of people who have survived SARS‐CoV‐2 infection, as well as for future public policy regarding infection mitigation. However, it will be critical to determine whether other agents known to increase risk for PD also have synergistic effects with SARS‐CoV‐2 and are abrogated by vaccination. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society