A restricted population of CB1 cannabinoid receptors with neuroprotective activity
A restricted population of CB1 cannabinoid receptors with neuroprotective activity
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DOI：
10.1073/pnas.1400988111
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发表时间：
2014-06-03
影响因子：
11.1
通讯作者：
Guzman, Manuel
中科院分区：
文献类型：
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作者：
Chiarlone, Anna;Bellocchio, Luigi;Guzman, Manuel
CB 1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点，是哺乳动物大脑中最丰富的G蛋白偶联受体。值得注意的是，CB 1受体在两个相对的（即，GABA能/抑制性和谷氨酸能/兴奋性）神经元群体，因此一种和/或另一种受体群体的激活可以想象地引起不同的效应。尽管在动物模型中广泛报道了CB 1受体的神经保护活性，但这两种CB 1受体池在神经退行性过程中的确切病理生理学相关性尚不清楚。在这里，我们首先诱导小鼠脑兴奋性毒性损伤，（i）给药喹啉酸的条件突变动物缺乏CB 1受体选择性的GABA能或谷氨酸能神经元，和（ii）操纵皮质纹状体谷氨酸能的预测远程设计受体专门激活设计药物药理遗传学方法。我们接下来检查了在R6/2小鼠中发生的改变，R6/2小鼠是一种成熟的亨廷顿病模型，在（i）完全敲除CB 1受体和（ii）选择性地删除皮质纹状体谷氨酸能或纹状体GABA能神经元中的CB 1受体后。这些数据明确地确定了位于大麻能末端的CB 1受体的有限群体是（内）大麻素神经保护活性中不可或缺的参与者，因此表明这种精确的受体库构成了神经保护治疗策略的有希望的靶点。
The CB1 cannabinoid receptor, the main molecular target of endo-cannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo) cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.