Neuropeptide and cytokines expression in long COVID-19 related neuropsychological sequelae: insights into NK1R-mediated neuroinflammation and in silico therapeutic targeting

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Background Long COVID-19 causes neurophysiological, cardiopulmonary, and musculoskeletal issues. Increased neuropeptides and cytokines lead to neuroinflammation, resulting in neurocognitive impairments, fatigue, depression, anxiety, and severe cognitive deficits. The Neurokinin 1 receptor (NK1R) is a cellular receptor for the neuropeptide Substance P, and its dysregulation links to neuropsychological issues despite antipsychotic use. Objectives In the present study, neuropsychological sequelae related to long COVID-19 were screened and the expression of related neuropeptides and cytokines was evaluated. Additionally, potential drugs have been evaluated computationally to reduce neuroinflammation in long COVID-19. Methods After informed consent, subjects were screened by a medical physician for long COVID-19 in an outdoor patient clinic. Various biological scales were used to assess and categorize the severity of neuropsychological symptoms related to long COVID-19. After that, peripheral blood samples were collected from subjects using ELISA and RT-qPCR. Nine drugs were selected and subjected to virtual screening to identify potential drug antagonists for NK1R. The key drug-like properties, safety profile, pharmacokinetic analysis, and biological activity of the identified hits were assessed. Results In this study the mean age of 90 patients (60% males and 40% females), was 33 ± 5 years in the symptomatic group and 31 ± 6 years in the asymptomatic long COVID-19 group for <40 years age-group. Whereas, the mean age of >40 years age-group was 58 ± 10 years in the symptomatic group and 54 ± 11 years in the asymptomatic long COVID-19 group. The minimum persistence of duration of long COVID-19 related symptoms in the <30 weeks group was observed to be 19 ± 6 weeks, while 44 ± 6 weeks in the >30 weeks group of symptomatic long COVID-19. A total of 48% patients had fatigue, 47% complained about headache, 28% had anxiety, 25% faced depression, 20% had psychosocial distress, 20% felt discomfort, and 13% had cognitive impairment. A total of 10% had reported dizziness sequelae among long COVID-19 survivors. Experimental data showed upregulation of IL-6, IL-10, and SP in both symptomatic and asymptomatic individuals compared with controls ( p < 0.001). Drug screening analyses revealed aprepitant (−9.3 kcal/mol) and N- acetyl- L- tryptophan (−8.7 kcal/mol) stable interactions with NK1R and maintaining molecular dynamics stability (RMSD: 1.5–2.2 Å; RMSF 0.8–1.4 Å; Rg approximately 21.6 Å). These compounds also demonstrated favorable blood-brain barrier permeability and pharmacokinetic profiles, suggesting their potential as therapeutic antagonists for treating prolonged COVID-related neuroinflammation. Conclusion IL-6, IL-10, and SP are found to be deregulated in long COVID-19 leading to neurophysiological sequelae. To overcome neuropsychological sequelae, binding of SP to NK1R can be hindered using aprepitant and N-Acetyl-L tryptophan which has been evaluated computationally and may require further in vivo and in vitro studies for validation.

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