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

DOI record: { "DOI": "10.3389/fncel.2026.1763029", "ISSN": [ "1662-5102" ], "URL": "http://dx.doi.org/10.3389/fncel.2026.1763029", "abstract": "<jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Objectives</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>\n 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 &amp;lt;40 years age-group. Whereas, the mean age of &amp;gt;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 &amp;lt;30 weeks group was observed to be 19 ± 6 weeks, while 44 ± 6 weeks in the &amp;gt;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 (\n <jats:italic>p</jats:italic>\n &amp;lt; 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.\n </jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusion</jats:title>\n <jats:p>\n 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\n <jats:italic>in vivo</jats:italic>\n and\n <jats:italic>in vitro</jats:italic>\n studies for validation.\n </jats:p>\n </jats:sec>", "alternative-id": [ "10.3389/fncel.2026.1763029" ], "article-number": "1763029", "author": [ { "affiliation": [ { "name": "Institute of Molecular Biology and Biotechnology, The University of Lahore", "place": [ "Lahore, Pakistan" ] } ], "family": "Abdullah", "given": "Muhammad", "sequence": "first" }, { "affiliation": [ { "name": "Institute of Molecular Biology and Biotechnology, The University of Lahore", "place": [ "Lahore, Pakistan" ] } ], "family": "Naz", "given": "Anam", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Physiological Sciences, The University of Florida", "place": [ "Gainesville, FL, United States" ] } ], "family": "Reznikov", "given": "Leah R.", "sequence": "additional" }, { "affiliation": [ { "name": "Institute of Molecular Biology and Biotechnology, The University of Lahore", "place": [ "Lahore, Pakistan" ] } ], "family": "Qureshi", "given": "Javed Anver", "sequence": "additional" }, { "affiliation": [ { "name": "Faculty of Biological Sciences, Lahore University of Biological and Applied Sciences", "place": [ "North Tulspura, Lahore, Pakistan" ] } ], "family": "Hasnain", "given": "Ammarah", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medical Lab Technology, The University of Haripur", "place": [ "Haripur, Pakistan" ] } ], "family": "Obaid", "given": "Ayesha", "sequence": "additional" }, { "affiliation": [ { "name": "University Institute of Physical Therapy, The University of Lahore", "place": [ "Lahore, Pakistan" ] } ], "family": "Ali", "given": "Amjed", "sequence": "additional" } ], "container-title": "Frontiers in Cellular Neuroscience", "container-title-short": "Front. 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Neurosci.", "content-domain": { "crossmark-restriction": true, "domain": [ "frontiersin.org" ] }, "created": { "date-parts": [ [ 2026, 3, 26 ] ], "date-time": "2026-03-26T05:18:59Z", "timestamp": 1774502339000 }, "deposited": { "date-parts": [ [ 2026, 3, 26 ] ], "date-time": "2026-03-26T05:19:06Z", "timestamp": 1774502346000 }, "indexed": { "date-parts": [ [ 2026, 3, 26 ] ], "date-time": "2026-03-26T07:27:53Z", "timestamp": 1774510073371, "version": "3.50.1" }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2026, 3, 26 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2026, 3, 26 ] ], "date-time": "2026-03-26T00:00:00Z", "timestamp": 1774483200000 } } ], "link": [ { "URL": "https://www.frontiersin.org/articles/10.3389/fncel.2026.1763029/full", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1965", "original-title": [], "prefix": "10.3389", "published": { "date-parts": [ [ 2026, 3, 26 ] ] }, "published-online": { "date-parts": [ [ 2026, 3, 26 ] ] }, "publisher": "Frontiers Media SA", "reference": [ { "DOI": "10.1038/s41591-024-03173-6", "article-title": "Long COVID science, research and policy", "author": "Al-Aly", "doi-asserted-by": "publisher", "first-page": "2148", "journal-title": "Nat. 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