通过大脑皮层大麻素受体和含胆碱脂质改善认知。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-11-03 DOI:10.1111/bph.17381
Marta Moreno-Rodríguez, Jonatan Martínez-Gardeazabal, Iker Bengoetxea de Tena, Alberto Llorente-Ovejero, Laura Lombardero, Estibaliz González de San Román, Lydia Giménez-Llort, Iván Manuel, Rafael Rodríguez-Puertas
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引用次数: 0

摘要

背景和目的:最近的研究表明,在神经病理状态下,含胆碱的脂质与基底前脑胆碱能神经元的变性有关,这说明了在脂质完整性与最佳乙酰胆碱水平之间取得平衡所面临的挑战,而乙酰胆碱对记忆的保存至关重要。内源性大麻素系统影响着由胆碱能神经传递调节的学习和记忆过程。因此,我们假设,激活内源性大麻素系统可能会对胆碱能退化产生神经保护作用:实验方法:我们利用包括大细胞基底核和皮层在内的体外器官组织培养物以及 192IgG-saporin 诱导的特定胆碱能损伤体内大鼠模型,研究了亚慢性大麻素激动剂 WIN55,212-2 治疗的神经保护潜力。脂质、胆碱和乙酰胆碱的水平是通过组织化学和免疫荧光测定法,以及大麻素和毒蕈碱类 GPCR 的 [35S]GTPγS 自显影和 MALDI 质谱成像分析来测量的。对大鼠和 3xTg-AD 小鼠模型的学习和记忆进行了巴恩斯迷宫和新物体识别测试评估:主要结果:192IgG-saporin诱导的皮层基底胆碱能通路退化导致记忆缺陷和皮层溶血磷脂酰胆碱(LPC)水平下降。WIN55,212-2通过激活大麻素受体恢复了大脑皮层的胆碱能传导和LPC水平。这种激活主要通过减少病变动物的鞘磷脂来改变大脑皮层的脂质平衡。这些改变对记忆恢复至关重要:我们假设,WIN55,212-2 可通过分解鞘磷脂促进胆碱替代来源,从而导致皮质乙酰胆碱水平和 LPCs 的升高。这些结果表明,通过激活大麻素受体来改变含胆碱脂质,是治疗与胆碱能功能障碍有关的痴呆症的一种很有前景的方法。
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Cognitive improvement via cortical cannabinoid receptors and choline-containing lipids.

Background and purpose: 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.

Experimental approach: 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 [35S]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.

Key results: 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.

Conclusion and implications: 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.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
期刊最新文献
Mu-opioid receptors in tachykinin-1-positive cells mediate the respiratory and antinociceptive effects of the opioid fentanyl. Issue Information Cognitive improvement via cortical cannabinoid receptors and choline-containing lipids. Have plastic culture models prevented the discovery of effective cancer therapeutics? Sex influence on serotonergic modulation of the vascular noradrenergic drive in rats.
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