{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T07:27:53Z","timestamp":1774510073371,"version":"3.50.1"},"reference-count":100,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"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 \u00b1 5 years in the symptomatic group and 31 \u00b1 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 \u00b1 10 years in the symptomatic group and 54 \u00b1 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 \u00b1 6 weeks, while 44 \u00b1 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 (\u22129.3 kcal\/mol) and N- acetyl- L- tryptophan (\u22128.7 kcal\/mol) stable interactions with NK1R and maintaining molecular dynamics stability (RMSD: 1.5\u20132.2 \u00c5; RMSF 0.8\u20131.4 \u00c5; Rg approximately 21.6 \u00c5). 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>","DOI":"10.3389\/fncel.2026.1763029","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T05:18:59Z","timestamp":1774502339000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuropeptide and cytokines expression in long COVID-19 related neuropsychological sequelae: insights into NK1R-mediated neuroinflammation and in silico therapeutic targeting"],"prefix":"10.3389","volume":"20","author":[{"given":"Muhammad","family":"Abdullah","sequence":"first","affiliation":[{"name":"Institute of Molecular Biology and Biotechnology, The University of Lahore","place":["Lahore, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anam","family":"Naz","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Biotechnology, The University of Lahore","place":["Lahore, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leah R.","family":"Reznikov","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, The University of Florida","place":["Gainesville, FL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javed Anver","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Biotechnology, The University of Lahore","place":["Lahore, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ammarah","family":"Hasnain","sequence":"additional","affiliation":[{"name":"Faculty of Biological Sciences, Lahore University of Biological and Applied Sciences","place":["North Tulspura, Lahore, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayesha","family":"Obaid","sequence":"additional","affiliation":[{"name":"Department of Medical Lab Technology, The University of Haripur","place":["Haripur, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amjed","family":"Ali","sequence":"additional","affiliation":[{"name":"University Institute of Physical Therapy, The University of Lahore","place":["Lahore, Pakistan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2148","DOI":"10.1038\/s41591-024-03173-6","article-title":"Long COVID science, research and policy","volume":"30","author":"Al-Aly","year":"2024","journal-title":"Nat. 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