Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, United Kingdom.
University Hospitals of Derby and Burton NHS Foundation Trust, Royal Derby Hospital, Derby, United Kingdom.
Cannabis Cannabinoid Res. 2021 Aug;6(4):315-326. doi: 10.1089/can.2020.0159. Epub 2021 Mar 17.
Preclinical studies have shown cannabidiol is protective in models of ischemic stroke. Based on results from our recent systematic review, we investigated the effects of two promising neuroprotective phytocannabinoids, cannabigerol (CBG) and cannabidivarin (CBDV), on cells of the blood-brain barrier (BBB), namely human brain microvascular endothelial cells (HBMECs), pericytes, and astrocytes. Cultures were subjected to oxygen-glucose deprivation (OGD) protocol to model ischemic stroke and cell culture medium was assessed for cytokines and adhesion molecules post-OGD. Astrocyte cell lysates were also analyzed for DNA damage markers. Antagonist studies were conducted where appropriate to study receptor mechanisms. In astrocytes CBG and CBDV attenuated levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH), whereas CBDV (10 nM-10 μM) also decreased vascular endothelial growth factor (VEGF) secretion. CBDV (300 nM-10 μM) attenuated levels of monocyte chemoattractant protein (MCP)-1 in HBMECs. In astrocytes, CBG decreased levels of DNA damage proteins, including p53, whereas CBDV increased levels of DNA damage markers. Antagonists for CB, CB, PPAR-γ, PPAR-α, 5-HT1, and TRPV1 had no effect on CBG (3 μM) or CBDV (1 μM)-mediated decreases in LDH in astrocytes. GPR55 and GPR18 were partially implicated in the effects of CBDV, but no molecular target was identified for CBG. We show that CBG and CBDV were protective against OG mediated injury in three different cells that constitute the BBB, modulating different hallmarks of ischemic stroke pathophysiology. These data enhance our understanding of the protective effects of CBG and CBDV and warrant further investigation into these compounds in ischemic stroke. Future studies should identify other possible neuroprotective effects of CBG and CBDV and their corresponding mechanisms of action.
临床前研究表明，大麻二酚在缺血性中风模型中具有保护作用。基于我们最近的系统评价结果，我们研究了两种有前途的神经保护植物大麻素，大麻萜酚（CBG）和大麻色原醇（CBDV）对血脑屏障（BBB）细胞的影响，即人脑微血管内皮细胞（HBMEC）、周细胞和星形胶质细胞。 培养物接受氧葡萄糖剥夺（OGD）方案模拟缺血性中风，OGD 后评估细胞培养液中的细胞因子和粘附分子。星形胶质细胞细胞裂解物也用于分析 DNA 损伤标志物。在适当的情况下进行拮抗剂研究以研究受体机制。 在星形胶质细胞中，CBG 和 CBDV 降低了白细胞介素 6（IL-6）和乳酸脱氢酶（LDH）的水平，而 CBDV（10 nM-10 μM）也降低了血管内皮生长因子（VEGF）的分泌。CBDV（300 nM-10 μM）降低了 HBMEC 中单核细胞趋化蛋白 1（MCP-1）的水平。在星形胶质细胞中，CBG 降低了包括 p53 在内的 DNA 损伤蛋白的水平，而 CBDV 增加了 DNA 损伤标志物的水平。CB（3 μM）或 CBDV（1 μM）介导的星形胶质细胞中 LDH 的降低不受 CB、CB、PPAR-γ、PPAR-α、5-HT1 和 TRPV1 拮抗剂的影响。GPR55 和 GPR18 部分参与了 CBDV 的作用，但未鉴定出 CBG 的分子靶标。 我们表明，CBG 和 CBDV 可防止 OG 介导的 BBB 三种不同细胞的损伤，调节缺血性中风病理生理学的不同特征。这些数据增强了我们对 CBG 和 CBDV 保护作用的理解，并证明了在缺血性中风中进一步研究这些化合物的合理性。未来的研究应确定 CBG 和 CBDV 的其他可能的神经保护作用及其相应的作用机制。
