{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T02:12:49Z","timestamp":1782958369184,"version":"3.54.5"},"reference-count":101,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Science, Innovation and Universities","award":["MICIU\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MICIU\/AEI\/10.13039\/501100011033"]}]},{"DOI":"10.13039\/501100004895","name":"ESF+","doi-asserted-by":"crossref","award":["PID2024-158925OB-I00"],"award-info":[{"award-number":["PID2024-158925OB-I00"]}],"id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004895","name":"ESF+","doi-asserted-by":"crossref","award":["PID2021-126600OBI00"],"award-info":[{"award-number":["PID2021-126600OBI00"]}],"id":[{"id":"10.13039\/501100004895","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is a progressive neurological disorder that affects movement, causing symptoms such as tremors, stiffness, slowness, and balance problems due to the degeneration of dopamine-producing neurons in the brain. Nowadays there is no cure for PD. Alpha synuclein (\u03b1-syn) aggregates, which are a hallmark of PD, are known to induce microglial activation, specifically the detrimental M1 microglial phenotype, which contributes to neuroinflammation and disease progression. Cannabinoid receptor 2 (CB2R) activation has been shown to counteract neuroinflammation. CB2R is able to interact with N-methyl-D-aspartate (NMDA) receptors (NMDAR), which has also attracted attention in PD research due to its role in excitotoxicity. Here we aimed to study the interaction between CB2R and NMDAR in a PD context in rat tissue. We observed that \u03b1-syn fibrils alter CB2R activation and CB2R-NMDAR heteromerization in a heterologous expression system. Furthermore, activation of CB2R counteracted NMDAR signaling. In microglia, \u03b1-syn fibrils decreased CB2R-NMDAR heteromer expression while increasing CB2R signaling. Importantly, CB2R activation counteracted the \u03b1-syn fibrils-induced increase in M1-activated microglia, while it favored the polarization of microglia to the beneficial M2 phenotype. These results reinforce the idea of using cannabinoids for treating PD, as they provide not only the anti-inflammatory effects of cannabinoids but also counteract the detrimental increase in NMDAR signaling present in this disease.<\/jats:p>","DOI":"10.3390\/ijms26199419","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T11:28:32Z","timestamp":1758886112000},"page":"9419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Interplay Between CB2 and NMDA Receptors in Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2077-2537","authenticated-orcid":false,"given":"Irene","family":"Reyes-Resina","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Institut de Neuroci\u00e8ncies UB, Campus Mundet, Passeig de la Vall d\u2019Hebron 171, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaume","family":"Lillo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Institut de Neuroci\u00e8ncies UB, Campus Mundet, Passeig de la Vall d\u2019Hebron 171, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iu","family":"Ra\u00efch","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Institut de Neuroci\u00e8ncies UB, Campus Mundet, Passeig de la Vall d\u2019Hebron 171, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan Biel","family":"Rebassa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Institut de Neuroci\u00e8ncies UB, Campus Mundet, Passeig de la Vall d\u2019Hebron 171, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni","family":"Cap\u00f3","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Institut de Neuroci\u00e8ncies UB, Campus Mundet, Passeig de la Vall d\u2019Hebron 171, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9272-562X","authenticated-orcid":false,"given":"Pau","family":"Badia","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4654-0873","authenticated-orcid":false,"given":"Gemma","family":"Navarro","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Network Center for Biomedical Research in Neurodegenerative Diseases, CiberNed, Spanish National Health Institute Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain"},{"name":"Institut de Neuroci\u00e8ncies UB, Campus Mundet, Passeig de la Vall d\u2019Hebron 171, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1212\/WNL.48.5.1277","article-title":"A Population Perspective on Diagnostic Criteria for Parkinson\u2019s Disease","volume":"48","author":"Rocca","year":"1997","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/ene.14108","article-title":"Parkinson Disease","volume":"27","author":"Balestrino","year":"2020","journal-title":"Eur. J. 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