Moreno-Rodríguez Marta, Martínez-Gardeazabal Jonatan, Bengoetxea de Tena Iker, Llorente-Ovejero Alberto, Lombardero Laura, González de San Román Estibaliz, Giménez-Llort Lydia, Manuel Iván, Rodríguez-Puertas Rafael
Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.
Department of Psychiatry and Forensic Medicine, School of Medicine & Institute of Neuroscience, Autonomous University of Barcelona (UAB), Barcelona, Spain.
Br J Pharmacol. 2025 Feb;182(4):1038-1058. doi: 10.1111/bph.17381. Epub 2024 Nov 3.
Recent research linking choline-containing lipids to degeneration of basal forebrain cholinergic neurons in neuropathological states illustrates the challenge of balancing lipid integrity with optimal acetylcholine levels, essential for memory preservation. 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.
We examined the neuroprotective potential of sub-chronic treatments with the cannabinoid agonist WIN55,212-2, using ex vivo organotypic tissue cultures including nucleus basalis magnocellularis and cortex and in vivo rat models of specific cholinergic damage induced by 192IgG-saporin. Levels of lipids, choline and acetylcholine were measured with histochemical and immunofluorescence assays, along with [S]GTPγS autoradiography of cannabinoid and muscarinic GPCRs and MALDI-mass spectrometry imaging analysis. Learning and memory were assessed by the Barnes maze and the novel object recognition test in rats and in the 3xTg-AD mouse model.
Degeneration, induced by 192IgG-saporin, of baso-cortical cholinergic pathways resulted in memory deficits and decreased cortical levels of lysophosphatidylcholines (LPC). WIN55,212-2 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.
We hypothesise that WIN55,212-2 facilitates an alternative choline source by breaking down sphingomyelins, leading to elevated cortical acetylcholine levels and LPCs. These results imply that altering choline-containing lipids via activation of cannabinoid receptors presents a promising therapeutic approach for dementia linked to cholinergic dysfunction.
近期研究表明，在神经病理状态下，含胆碱脂质与基底前脑胆碱能神经元的退化有关，这凸显了在维持脂质完整性与维持对记忆保存至关重要的最佳乙酰胆碱水平之间取得平衡的挑战。内源性大麻素系统影响由胆碱能神经传递调节的学习和记忆过程。因此，我们假设内源性大麻素系统的激活可能对胆碱能退化具有神经保护作用。
我们使用包括大细胞基底核和皮质的离体器官型组织培养以及由192IgG-皂草素诱导的特定胆碱能损伤的体内大鼠模型，研究了大麻素激动剂WIN55,212-2的亚慢性治疗的神经保护潜力。通过组织化学和免疫荧光测定法测量脂质、胆碱和乙酰胆碱的水平，同时对大麻素和毒蕈碱GPCR进行[S]GTPγS放射自显影以及基质辅助激光解吸电离质谱成像分析。通过巴恩斯迷宫和新物体识别测试评估大鼠和3xTg-AD小鼠模型中的学习和记忆。
由192IgG-皂草素诱导的基底-皮质胆碱能通路退化导致记忆缺陷和皮质溶血磷脂酰胆碱（LPC）水平降低。WIN55,212-2通过激活大麻素受体恢复了皮质胆碱能传递和LPC水平。这种激活主要通过减少受损动物中的鞘磷脂来改变皮质脂质稳态。这些改变对记忆恢复至关重要。
我们假设WIN55,212-2通过分解鞘磷脂促进了另一种胆碱来源，导致皮质乙酰胆碱水平和LPC升高。这些结果表明，通过激活大麻素受体改变含胆碱脂质是一种有前景的治疗与胆碱能功能障碍相关痴呆的方法。
