药理抑制 CB1 大麻受体可恢复大脑线粒体 CB1 受体的异常表达,并挽救雷特综合征雌性小鼠模型的生物能和认知缺陷。

IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Molecular Autism Pub Date : 2024-09-19 DOI:10.1186/s13229-024-00617-1
Livia Cosentino, Chiara Urbinati, Chiara Lanzillotta, Domenico De Rasmo, Daniela Valenti, Mattia Pellas, Maria Cristina Quattrini, Fabiana Piscitelli, Magdalena Kostrzewa, Fabio Di Domenico, Donatella Pietraforte, Tiziana Bisogno, Anna Signorile, Rosa Anna Vacca, Bianca De Filippis
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引用次数: 0

摘要

背景:线粒体缺陷和大脑线粒体生物能异常是综合智力障碍疾病的一致特征,如雷特综合征(RTT),这是一种罕见的神经系统疾病,主要严重影响携带 X 连锁 MECP2 基因突变的女性。CB1大麻素受体(CB1R)是脑内大麻素系统的主要受体亚型,它位于脑线粒体膜(mtCB1R)上,可通过抑制线粒体内蛋白激酶A(mtPKA)局部调节能量产生、突触传递和记忆能力。在本研究中,我们提出了一个问题:mtCB1R-mtPKA 信号过度活跃是否可能是 RTT 中大脑线粒体改变的基础,以及通过全身给药 CB1R 反向激动剂利莫那班是否可能改善 RTT 模型小鼠的生物能和认知缺陷:结果:mtCB1R在RTT小鼠大脑中过度表达。使用利莫那班进行亚慢性治疗可使 RTT 小鼠大脑中的 mtCB1R 表达正常化,促进 mtPKA 信号传导,恢复 RTT 小鼠大脑线粒体生物能缺陷、外周氧化还原平衡异常和认知能力受损:局限性:由于利莫那班治疗对 mtCB1R 缺乏选择性,我们不能排除在 RTT 小鼠模型中治疗产生的有益效应可能更广泛地归因于对 CB1R 活性和在细胞内各区室分布的调节,而不是对 mtCB1R 介导的信号传导的选择性效应。少数实验的样本量较少是另一个限制因素,在不同的实验条件下复制主要发现可以解决这个问题:本研究数据发现,mtCB1R 过表达是 RTT 小鼠大脑中的一种新的分子改变,可能是大脑线粒体生物能缺陷和认知功能障碍的基础。
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Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome.

Background: Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT.

Methods: Rimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed.

Results: mtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice.

Limitations: The lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions.

Conclusions: The present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction.

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来源期刊
Molecular Autism
Molecular Autism GENETICS & HEREDITY-NEUROSCIENCES
CiteScore
12.10
自引率
1.60%
发文量
44
审稿时长
17 weeks
期刊介绍: Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.
期刊最新文献
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