Therapy for long-COVID in a preclinical model

ABSTRACT New SARS-CoV-2 variants and novel coronaviruses will constantly arise and affect large proportions of the worldwide population. Although the current wave of infections with Omicron subvariants is much less lethal than that caused by previous SARS-CoV-2 variants (e.g., Wuhan-Hu1, Alpha, and Delta), about 10% of Omicron- infected patients develop prolonged post-acute neurological sequelae involving cognitive impairments ("brain fog"), difficulty concentrating, anxiety, and depression. Histological studies of brains from COVID-19 patients have often observed immune cell infiltrates and increased frequencies of glial cells with inflammatory phenotypes indicative of neuroinflammatory responses. Currently, there are no approved prophylactic or interventive treatments for SARS-CoV-2-induced neuroinflammation. There is a growing body of evidence that immune cells, microglia, and astrocytes express γ -aminobutyric acid receptors (GABAA-Rs). The activation of these GABAA-Rs inhibits their pro-inflammatory activities and shifts T cells, antigen-presenting cells, microglia, and astrocytes toward anti-inflammatory phenotypes. Taking advantage of these properties, researchers have used homotaurine, a clinically applicable GABAA-R agonist that can cross the blood-brain-barrier, to 1) reverse experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS) and 2) reduce the levels inflammatory cytokines in the CNS, decrease neuronal loss, and ameliorate behavioral deficits in a model of autism spectrum disorder. Furthermore, we have shown that GABAA- R agonists reduce circulating proinflammatory cytokines/chemokines, viral replication in the lungs, the severity of illness, and death in mice infected with two different coronaviruses: MHV-1 and SARS-CoV-2. Additionally, in clinical trials, homotaurine treatment has had some promising beneficial effects in Alzheimer's disease patients. We contend that homotaurine is an excellent candidate for preventing and ameliorating SARS-CoV-2- induced neuroinflammation. We will test this hypothesis in the hamster model of long COVID, arguably the best rodent model available at this time. We anticipate that we will demonstrate the potential of an entirely new drug class to help prevent and ameliorate SARS-CoV-2-induced neuroinflammation. Because homotaurine is safe for human consumption, it could be rapidly tested in clinical trials. Since the mechanism evoked by GABAA-R activation is unlike that of any other drugs being considered for treating long COVID, GABAA-R agonists are likely to have enhanced therapeutic effects when combined with other treatments. Finally, the results may have broader applications to treat other conditions involving CNS inflammation. Therefore, the results of our studies may provide novel approaches to help improve the health of the global community.