Amantadine Treatment for Parkinson’s Disease during COVID-19: Bimodal Action Targeting Viral Replication and the NMDA Receptor

Abstract

Parkinson’s Disease [PD] and COVID-19 share common features that include age dependency and their association with co-morbidities such as cardiovascular disease, diabetes and respiratory problems. Shortness of breath [dyspnea] is a feature of both conditions. Symptoms of PD are known to deteriorate during systemic infections and common features of COVID-19 [fever, delirium, stress] may aggravate tremor, gait and dyskinesias in PD. Parkinsonism is a feature of many viral encephalatides with associated basal ganglia neuropathology. Following uptake from the circulation or via the upper nasal transcribial route, the spike protein of SARS-CoV-2 binds to a host cell protein ACE2 expressed on neurons and neuroglia. Essential host cell proteases such as Cathepsin L [CTSL] then cleave the spike protein leading to fusion of viral and host cell membranes and release of the viral genome into the host cell. Cryo-microscopic studies confirm that SARS-CoV-2 binds with high affinity to ACE2. High throughput drug screen gene expression analysis of 466 agents with the potential to down-regulate expression of CTSL identified amantadine which ranked 5th in efficacy. A link between viral infection and treatment of PD by amantadine started serendipitously with the report of a PD patient noting improvement of tremor and rigidity after treatment with amantadine for influenza A infection. Amantadine’s beneficial action in PD relates to its ability to indirectly replenish dopaminergic activity via stimulation of the NMDA subclass of ionotropic glutamate receptors. An NMDA receptor antagonist was effective in limiting viral replication with improvement of neurological symptoms due to infection with HCoV-OC43. The ability of amantadine to exert beneficial effects in COVID-19 is worthy of clinical investigation.