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The endocannabinoid system influences learning and memory processes regulated by cholinergic neurotransmission. Therefore, we hypothesised that activation of the endocannabinoid system may confer neuroprotection against cholinergic degeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We examined the neuroprotective potential of sub\u2010chronic treatments with the cannabinoid agonist WIN55,212\u20102, using\n                      <jats:italic>ex vivo<\/jats:italic>\n                      organotypic tissue cultures including nucleus basalis magnocellularis and cortex and\n                      <jats:italic>in vivo<\/jats:italic>\n                      rat models of specific cholinergic damage induced by 192IgG\u2010saporin. Levels of lipids, choline and acetylcholine were measured with histochemical and immunofluorescence assays, along with [\n                      <jats:sup>35<\/jats:sup>\n                      S]GTP\u03b3S autoradiography of cannabinoid and muscarinic GPCRs and MALDI\u2010mass spectrometry imaging analysis. Learning and memory were assessed by the Barnes maze and the novel object recognition test in rats and in the 3xTg\u2010AD mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Degeneration, induced by 192IgG\u2010saporin, of baso\u2010cortical cholinergic pathways resulted in memory deficits and decreased cortical levels of lysophosphatidylcholines (LPC). WIN55,212\u20102 restored cortical cholinergic transmission and LPC levels via activation of cannabinoid receptors. This activation altered cortical lipid homeostasis mainly by reducing sphingomyelins in lesioned animals. These modifications were crucial for memory recovery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>We hypothesise that WIN55,212\u20102 facilitates an alternative choline source by breaking down sphingomyelins, leading to elevated cortical acetylcholine levels and LPCs. These results imply that altering choline\u2010containing lipids via activation of cannabinoid receptors presents a promising therapeutic approach for dementia linked to cholinergic dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.17381","type":"journal-article","created":{"date-parts":[[2024,11,3]],"date-time":"2024-11-03T21:50:38Z","timestamp":1730670638000},"page":"1038-1058","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cognitive improvement via cortical cannabinoid receptors and choline\u2010containing lipids"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9980-9365","authenticated-orcid":false,"given":"Marta","family":"Moreno\u2010Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0701-9076","authenticated-orcid":false,"given":"Jonatan","family":"Mart\u00ednez\u2010Gardeazabal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0586-1857","authenticated-orcid":false,"given":"Iker","family":"Bengoetxea de Tena","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8536-197X","authenticated-orcid":false,"given":"Alberto","family":"Llorente\u2010Ovejero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Lombardero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5440-2695","authenticated-orcid":false,"given":"Estibaliz","family":"Gonz\u00e1lez de San Rom\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydia","family":"Gim\u00e9nez\u2010Llort","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Forensic Medicine, School of Medicine &amp; Institute of Neuroscience Autonomous University of Barcelona (UAB)  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0958-4738","authenticated-orcid":false,"given":"Iv\u00e1n","family":"Manuel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa Spain"},{"name":"Neurodegenerative Diseases BioBizkaia Health Research Institute  Barakaldo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4517-5114","authenticated-orcid":false,"given":"Rafael","family":"Rodr\u00edguez\u2010Puertas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa Spain"},{"name":"Neurodegenerative Diseases BioBizkaia Health Research Institute  Barakaldo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,11,3]]},"reference":[{"issue":"2","key":"e_1_2_12_2_1","first-page":"S23","article-title":"The concise guide to PHARMACOLOGY 2023\/24: G protein\u2010coupled receptors","volume":"180","author":"Alexander S. 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