{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T15:54:24Z","timestamp":1773590064734,"version":"3.50.1"},"reference-count":120,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T00:00:00Z","timestamp":1749772800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: The blood\u2013brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) but also limits drug delivery. Insufficient knowledge of how the CNS promotes the onset and maintenance of peripheral neuropathic pain limits therapeutic methods for the treatment of persistent neuropathic pain. Thus, this study aimed to evaluate the ability of a novel combination of Palmitoylethanolamide (PEA) and Equisetum arvense L. (Equisetum A.L.) to cross the BBB and modulate nociceptive pathways. Methods: Using a humanised in vitro BBB tri-culture model, the permeability, cytotoxicity, and integrity of the barrier were assessed after exposure to two different PEA forms, PEA ultramicronized (PEA-um) and PEA80mesh, Equisetum A.L., and a combination of the last two samples. The samples exhibited no cytotoxicity, maintained tight junction integrity, and efficiently crossed the blood\u2013brain barrier (BBB), with the combination displaying the highest permeability. The eluate from the BBB model was then used to stimulate the co-culture of CCF-STTG1 astrocytes and SH-SY5Y neurons pre-treated with H2O2 200 \u00b5M. Results: Treatment with the combination significantly increased cell viability (1.8-fold, p &lt; 0.05), reduced oxidative stress (2.5-fold, p &lt; 0.05), and decreased pro-inflammatory cytokines (TNF\u03b1, IL-1\u03b2) compared to single agents. Mechanistic analysis revealed modulation of key targets involved in pain pathways, including decreased FAAH and NAAA activity, increased levels of endocannabinoids (AEA and 2-AG), upregulation of CB2 receptor expression, enhanced PPAR\u03b1 activity, and reduced phosphorylation of PKA and TRPV1. Conclusions: These findings suggest that the combination of PEA and Equisetum A.L. effectively crosses the BBB and exerts combined anti-inflammatory and analgesic effects at the CNS level, suggesting a possible role in modulating neuroinflammatory and nociception responses.<\/jats:p>","DOI":"10.3390\/nu17121998","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T09:51:24Z","timestamp":1749808284000},"page":"1998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Molecular Insights into the Nociceptive Modulation by Palmitoylethanolamide and Equisetum arvense Extract: An In Vitro Study Across the Blood\u2013Brain Barrier"],"prefix":"10.3390","volume":"17","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":"Rebecca","family":"Galla","sequence":"additional","affiliation":[{"name":"Noivita Srls, Spin Off, University of Piemonte Orientale, Strada Privata Curti 7, 28100 Novara, 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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5141-0681","authenticated-orcid":false,"given":"Marco","family":"Invernizzi","sequence":"additional","affiliation":[{"name":"Physical and Rehabilitation Medicine, Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy"},{"name":"Translational Medicine, Dipartimento Attivit\u00e0 Integrate Ricerca e Innovazione (DAIRI), Azienda Ospedaliero-Universitaria (AOU) SS, Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, 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":[[2025,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/ana.23648","article-title":"The blood\u2013brain barrier in health and disease","volume":"72","author":"Daneman","year":"2012","journal-title":"Ann. 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