{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:41:50Z","timestamp":1791236510569,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"C.N.R project NutrAge","award":["DBA.AD005.225.001"],"award-info":[{"award-number":["DBA.AD005.225.001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent advances in cannabinoid-based therapies identified the natural CB2 receptor agonist \u03b2-caryophyllene (BCP) as a promising anti-inflammatory and neuroprotective agent. To further explore its therapeutic potential on the management of neurodegenerative disorders, in the present study we investigated the ability of BCP to prevent neuroinflammation and promote neuroprotection by using both in vitro and ex vivo models of \u03b2-amyloid induced neurotoxicity. Our data showed that BCP significantly protected human microglial HMC3 cells from A\u03b225-35-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-\u03b1, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-\u03baB pathway, which emerged as a central mediator of BCP action. Notably, the use of CB2R- or PPAR\u03b3-selective antagonists revealed that the observed NF-\u03baB inhibition by BCP may involve the coordinated activation of both canonical (e.g., CB2R) and non-canonical (e.g., PPAR\u03b3) receptors. Moreover, BCP restored the expression of SIRT1, PGC-1\u03b1, and BDNF, indicating the involvement of neurotrophic pathways. Clear neuroprotective properties for BCP have been highlighted in A\u03b21-42-treated brain slice preparations, where BCP demonstrated the rescue of both the amyloid-dependent depression of BDNF expression and long-term synaptic potentiation (LTP) impairment. Overall, our results suggest that BCP constitutes an attractive natural molecule for the treatment of A\u03b2-induced neuroinflammation and synaptic dysfunction, warranting further exploration for its clinical application.<\/jats:p>","DOI":"10.3390\/ijms26136027","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T06:49:38Z","timestamp":1750747778000},"page":"6027","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Multi-Target Protective Effects of \u03b2-Caryophyllene (BCP) at the Intersection of Neuroinflammation and Neurodegeneration"],"prefix":"10.3390","volume":"26","author":[{"given":"Caterina","family":"Ricardi","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Mazzierli","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8892-966X","authenticated-orcid":false,"given":"Stefano","family":"Guglielmo","sequence":"additional","affiliation":[{"name":"BIO@SNS Laboratory, Scuola Normale Superiore, Via Moruzzi 1, 56124 Pisa, Italy"},{"name":"Institute of Neuroscience, Italian National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4037-881X","authenticated-orcid":false,"given":"Nicola","family":"Origlia","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, Italian National Research Council (CNR), 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2971-0834","authenticated-orcid":false,"given":"Francesca","family":"Gado","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clementina","family":"Manera","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6703-5820","authenticated-orcid":false,"given":"Grazia","family":"Chiellini","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-6091","authenticated-orcid":false,"given":"Beatrice","family":"Polini","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Grabon, W., Rheims, S., Smith, J., Bodennec, J., Belmeguenai, A., and Bezin, L. 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