{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T09:42:00Z","timestamp":1766050920919,"version":"build-2065373602"},"reference-count":108,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T00:00:00Z","timestamp":1762560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pain remains a major clinical challenge due to its complex physiopathology and limited treatment options. In this context, several supplements based on palmitoylethanolamide (PEA) and alpha-lipoic acid (ALA) are known for their neuroprotective properties. ALA-based supplements have shown potential, but concerns about adverse effects persist. This study examines the formulations of two commercial products based on ALA and PEA, IperALA\u00ae and IperALA\u00ae Forte, in which ALA and vitamin D3 are replaced with Coriandrum sativum extract (C. sativum e.s.), N-acetylcysteine (NAC) and glutathione (GSH), assessing improvement of neuroprotective, anti-inflammatory and analgesic properties of the new formulation. Intestinal, blood\u2013brain barrier (BBB), and central nervous system (CNS) models were sequentially stimulated with the test compounds. Both formulations were assessed for cytotoxicity, barrier integrity, permeability, oxidative stress, inflammation, and neuroprotection-related biomarkers. IperALA\u00ae Forte demonstrated superior performance compared to IperALA\u00ae and individual agents. It enhanced cell viability, preserved intestinal and BBB integrity, and improved compound permeability. Notably, it reduced ROS and pro-inflammatory cytokines (TNF\u03b1, IL-1), while increasing analgesic markers (CB2R, GABA) in the central system. The replacement of ALA and vitamin D3 with C. sativum, NAC, and GSH in IperALA\u00ae Forte significantly improved the neuroprotective, antioxidant, and anti-inflammatory profile of the supplement. These results indicate a possible connection between the observed neuroprotective properties and the pathways involved in nociception and pain regulation, stating the hypothetical potential relevance of this approach for the treatment of pain-related conditions.<\/jats:p>","DOI":"10.3390\/ijms262210857","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T08:57:55Z","timestamp":1762765075000},"page":"10857","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neuroprotective Pathway Modulation by a Novel Coriandrum sativum, N-Acetylcysteine and Glutathione-Based Formulation: Insights from In Vitro 3D Models"],"prefix":"10.3390","volume":"26","author":[{"given":"Simone","family":"Mul\u00e8","sequence":"first","affiliation":[{"name":"Department for Sustainable Development and Ecological Transition, University of Piemonte Orientale (UPO), 13100 Vercelli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Department for Sustainable Development and Ecological Transition, University of Piemonte Orientale (UPO), 13100 Vercelli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Galla","sequence":"additional","affiliation":[{"name":"Noivita Srls, Spin Off, University of Piemonte Orientale (UPO), Strada Privata Curti 7, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5751-270X","authenticated-orcid":false,"given":"Francesca","family":"Uberti","sequence":"additional","affiliation":[{"name":"Department for Sustainable Development and Ecological Transition, University of Piemonte Orientale (UPO), 13100 Vercelli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"867","DOI":"10.2147\/JPR.S348324","article-title":"Nociceptors: Their Role in Body\u2019s Defenses, Tissue Specific Variations and Anatomical Update","volume":"15","author":"Nikolenko","year":"2022","journal-title":"J. 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