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In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine\u2010loaded nanostructured lipid carriers (AGM\u2010NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM\u2010NLCs, which were administered at 20\u2009mg\/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)\u20101\u03b2 and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase\u20101 (HO\u20101) and nuclear factor E2\u2010related factor (Nrf2). Treatment with AGM and AGM\u2010NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM\u2010NLCs, all\u2010trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO\u20101 expressions were significantly upregulated after AGM\u2010NLCs administration. Overall, the results demonstrated that AGM\u2010NLCs offer promising antinociceptive and anti\u2010inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone.<\/jats:p>","DOI":"10.1111\/1440-1681.13922","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:10:12Z","timestamp":1727741412000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Agomelatine\u2010loaded nanostructured lipid carriers alleviate neuropathic pain in rats by Nrf2\/<scp>HO<\/scp>\u20101 signalling pathway"],"prefix":"10.1111","volume":"51","author":[{"given":"Sundas","family":"Firdoos","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceutical Beijing Institute of Technology (BIT)  Beijing People's Republic of China"},{"name":"Department 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Bin Abdulaziz University  Al\u2010Kharj Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maleeha","family":"Gul","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences Riphah International University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madiha","family":"Rasheed","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceutical Beijing Institute of Technology (BIT)  Beijing People's Republic of 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