{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:09:21Z","timestamp":1790114961601,"version":"4.0.1"},"reference-count":63,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011821","name":"Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia","doi-asserted-by":"publisher","award":["IFPRC-168-141-2020"],"award-info":[{"award-number":["IFPRC-168-141-2020"]}],"id":[{"id":"10.13039\/501100011821","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Demyelination and neuroinflammation are central features of multiple sclerosis (MS), contributing to motor deficits and cognitive decline. Cuprizone (CPZ)-induced demyelination is a well-established model for studying multiple sclerosis-like neurotoxicity. This study investigated the neuroprotective and immunomodulatory effects of self-nanoemulsifying drug delivery systems (SNEDDSs) incorporating curcumin, piperine, and Zanthoxylum rhetsa seed oil. Methods: Male mice were divided into five groups: control, CPZ-only, and CPZ co-treated with three nanoformulations BFZ (blank SNEDDS), CFZ (curcumin-SNEDDS), and PFZ (curcumin\u2013piperine SNEDDS). CPZ was administered for 5 weeks, followed by a 2-week recovery or treatment phase. Key neuroinflammatory markers like CD4, CD8, cholinergic (acetylcholinesterase, AChE), myelin integrity (MBP), BDNF, CREB, TNF\u03b1, Il-1\u03b2 were assessed at weeks 5 and 7 using ELISA. Alterations in antioxidant enzymes, brain histology, and behavioral outcomes were also investigated. Results: At week 5, CPZ significantly increased CD4 and CD8 expression and reduced AChE and MBP levels, indicating neuroinflammation, cholinergic impairment, and demyelination. Nanoformulation treatments (both prophylactic and therapeutic) markedly reduced CD4 and CD8 levels, with PFZ showing the most pronounced effect. AChE activity was significantly restored in all treatment groups, with PFZ and CFZ exceeding baseline levels, suggesting enhanced cholinergic function. MBP levels were highest in PFZ-treated mice, surpassing control values and indicating strong remyelination potential. These improvements persisted and further advanced at week 7, especially in PFZ and CFZ groups. Conclusions: Curcumin-based SNEDDS, particularly PFZ, significantly mitigated CPZ-induced neuroinflammation, promoted remyelination, and restored cholinergic activity in the frontal cortex. These findings highlight the therapeutic potential of bioenhanced curcumin nanoformulations for treating demyelinating and neuroinflammatory disorders.<\/jats:p>","DOI":"10.3390\/ph18101478","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T07:58:13Z","timestamp":1759305493000},"page":"1478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Curcumin\u2013Piperine Self-Nanoemulsifying Delivery in Zanthoxylum rhetsa Seed Oil Attenuates Cuprizone-Induced Frontal Cortex Toxicity"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2843-169X","authenticated-orcid":false,"given":"Mohammad Zubair","family":"Alam","sequence":"first","affiliation":[{"name":"Neuroscience and Geroscience Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala Abubaker","family":"Bagabir","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, King Abdulaziz University, Rabigh 25732, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Alameen Faisal","family":"Zaher","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4466-7432","authenticated-orcid":false,"given":"Thamer M. A.","family":"Alqurashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Rabigh 25732, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Badrah S.","family":"Alghamdi","sequence":"additional","affiliation":[{"name":"Neuroscience and Geroscience Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Neuroscience Unit, Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5611-0378","authenticated-orcid":false,"given":"Mohsin","family":"Kazi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0398-0297","authenticated-orcid":false,"given":"Gamal Said Abd","family":"El-Aziz","sequence":"additional","affiliation":[{"name":"Department of Clinical Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7493-7224","authenticated-orcid":false,"given":"Gadah Ali","family":"Alshahrany","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor Ahmed","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafal Mohammed","family":"Bakhalgi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3071-6854","authenticated-orcid":false,"given":"Mona","family":"Al-Thepyani","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Sciences & Arts, King Abdulaziz University, Rabigh 25732, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7076-8491","authenticated-orcid":false,"given":"Hanin Abdulbaset","family":"AboTaleb","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahaf Saeed","family":"Aldhahri","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"Department of Biological Sciences, Faculty of Sciences, University of Jeddah, Djedda 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0872-0382","authenticated-orcid":false,"family":"Juweiriya","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9820-2078","authenticated-orcid":false,"given":"Ghulam Md","family":"Ashraf","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman P.O. 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