Greco Rosaria, Demartini Chiara, Zanaboni Annamaria, Tumelero Elena, Elisa Candeloro, Persico Alessandra, Morotti Andrea, Amantea Diana, Tassorelli Cristina
IRCCS Mondino Foundation, Via Mondino, 2, 27100, Pavia, Italy.
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
Transl Stroke Res. 2021 Aug;12(4):550-558. doi: 10.1007/s12975-020-00851-8. Epub 2020 Sep 22.
Both preclinical and clinical evidence supports the involvement of the endocannabinoid system in the pathobiology of cerebral ischemia. Selective cannabinoid-2 (CB2) receptor agonists exert significant neuroprotection in animal models of focal brain ischemia through a robust anti-inflammatory effect, involving both resident and peripheral immune cells. Nevertheless, no definitive studies demonstrating the relevance of CB2 receptors in human stroke exist.Using rtPCR and flow cytometry assays, we investigated CB2 receptor expression in circulating monocytes from 26 acute ischemic stroke patients and 16 age-matched healthy controls (CT). We also evaluated miR-665 expression, as potential CB2 receptor regulator. The median mRNA levels of CB2 were significantly (p < 0.0001) increased in total monocytes 24 h and 48 h after stroke as compared with CT. This was paralleled by elevation of miR-665 levels in monocytes collected from patients 24 h (p < 0.05 vs CT) and 48 h (p < 0.05 vs CT and p < 0.0001 vs 24 h) after ischemic stroke. Furthermore, an increased percentage of CB2+/CD16+ events, but not CB2+/CD14+ events, was found 24 h [20.17% (IQR, 17.22-23.58)] and 48 h [18.61% (IQR, 15.44-22.06)] after ischemic stroke when compared with CT [10.96% (IQR, 9.185-13.32)]. The percentage of CB2+/CD16+ events in monocytes was positively correlated with NIHSS score at entrance (r = 0.4327, p = 0.027). The potential beneficial functions of CD16+ intermediate and nonclassical monocytes in stroke and the elevated expression of CB2 receptor in these subsets strongly suggest that CB2 receptor agonists can be exploited for the treatment of ischemic stroke patients.
临床前和临床证据均支持内源性大麻素系统参与脑缺血的病理生物学过程。选择性大麻素-2（CB2）受体激动剂通过强大的抗炎作用，在局灶性脑缺血动物模型中发挥显著的神经保护作用，这一过程涉及驻留免疫细胞和外周免疫细胞。然而，尚无确凿研究证明CB2受体在人类中风中的相关性。
我们使用逆转录聚合酶链反应（rtPCR）和流式细胞术检测，对26例急性缺血性中风患者及16例年龄匹配的健康对照者（CT）循环单核细胞中的CB2受体表达进行了研究。我们还评估了作为潜在CB2受体调节剂的miR-665的表达情况。与CT相比，中风后24小时和48小时，总单核细胞中CB2的mRNA水平显著升高（p < 0.0001）。这与缺血性中风后24小时（与CT相比，p < 0.05）和48小时（与CT相比，p < 0.05；与24小时相比，p < 0.0001）患者单核细胞中miR-665水平升高相平行。此外，与CT [10.96%（四分位间距，9.185 - 13.32）]相比，缺血性中风后24小时[20.17%（四分位间距，17.22 - 23.58）]和48小时[18.61%（四分位间距，15.44 - 22.06）]发现CB2+/CD16+事件的百分比增加，但CB2+/CD14+事件未增加。单核细胞中CB2+/CD16+事件的百分比与入院时的美国国立卫生研究院卒中量表（NIHSS）评分呈正相关（r = 0.4327，p = 0.027）。CD16+中间型和非经典单核细胞在中风中的潜在有益功能以及这些亚群中CB2受体表达的升高强烈表明，CB2受体激动剂可用于治疗缺血性中风患者。
