The CB₁ cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway.
The CB₁ cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway.
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DOI：
10.1038/cdd.2015.11
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发表时间：
2015-10
影响因子：
12.4
通讯作者：
Guzmán M
中科院分区：
文献类型：
--
作者：
Blázquez C;Chiarlone A;Bellocchio L;Resel E;Pruunsild P;García-Rincón D;Sendtner M;Timmusk T;Lutz B;Galve-Roperh I;Guzmán M
CB1大麻素受体是内源性大麻素和大麻活性成分的主要分子靶标，是哺乳动物大脑中最丰富的G蛋白偶联受体。特别是，CB1受体在基底神经节中高度表达，主要在中等大小的多棘神经元的末端，在那里发挥着关键的神经调节功能。 CB1 受体还在各种纹状体损伤实验模型中提供神经保护作用。然而，由于缺乏对 CB1 受体神经保护活性精确机制的了解，对 CB1 受体在基底神经节相关疾病中的生理相关性和治疗潜力的评估受到阻碍，至少部分受到阻碍。在这里，通过使用一系列药理学、遗传学和药物遗传学（仅由设计药物激活的设计受体）方法，我们表明（1）CB1受体的参与通过雷帕霉素复合物1途径的磷脂酰肌醇3激酶/Akt/哺乳动物靶点保护纹状体细胞免受兴奋性毒性死亡，反过来，（2）通过选择性激活BDNF基因启动子IV诱导脑源性神经营养因子（BDNF）表达，一种效应这是由多种转录因子介导的。为了评估 CB1/BDNF 轴在体内神经退行性疾病背景下可能的功能影响，我们在 R6/2 小鼠中进行了实验，R6/2 小鼠是一种成熟的亨廷顿病模型，已知其中 CB1 受体和 BDNF 在背外侧纹状体中严重下调。腺相关病毒载体在 R6/2 小鼠的背外侧纹状体中强制重新表达 CB1 受体，从而使 BDNF 重新表达并协调拯救这些动物的神经病理缺陷。总的来说，这些发现揭示了 CB1 受体激活和 BDNF 表达之间的分子联系，并支持 CB1/BDNF 轴在促进纹状体神经元存活中的相关性。
The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. In particular, the CB1 receptor is highly expressed in the basal ganglia, mostly on terminals of medium-sized spiny neurons, where it plays a key neuromodulatory function. The CB1 receptor also confers neuroprotection in various experimental models of striatal damage. However, the assessment of the physiological relevance and therapeutic potential of the CB1 receptor in basal ganglia-related diseases is hampered, at least in part, by the lack of knowledge of the precise mechanism of CB1 receptor neuroprotective activity. Here, by using an array of pharmacological, genetic and pharmacogenetic (designer receptor exclusively activated by designer drug) approaches, we show that (1) CB1 receptor engagement protects striatal cells from excitotoxic death via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) expression through the selective activation of BDNF gene promoter IV, an effect that is mediated by multiple transcription factors. To assess the possible functional impact of the CB1/BDNF axis in a neurodegenerative-disease context in vivo, we conducted experiments in the R6/2 mouse, a well-established model of Huntington's disease, in which the CB1 receptor and BDNF are known to be severely downregulated in the dorsolateral striatum. Adeno-associated viral vector-enforced re-expression of the CB1 receptor in the dorsolateral striatum of R6/2 mice allowed the re-expression of BDNF and the concerted rescue of the neuropathological deficits in these animals. Collectively, these findings unravel a molecular link between CB1 receptor activation and BDNF expression, and support the relevance of the CB1/BDNF axis in promoting striatal neuron survival.