Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Department of Anatomy, School of Basic Medical Science, Zhejiang University School of Medicine, Hangzhou, 310058, China.
College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Acta Pharmacol Sin. 2022 Jan;43(1):15-25. doi: 10.1038/s41401-021-00637-0. Epub 2021 Apr 6.
White matter injury is the major pathological alteration of subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion. It is characterized by progressive demyelination, apoptosis of oligodendrocytes and microglial activation, which leads to impairment of cognitive function. Triptolide exhibits a variety of pharmacological activities including anti-inflammation, immunosuppression and antitumor, etc. In this study, we investigated the effects of triptolide on white matter injury and cognitive impairments in mice with chronic cerebral hypoperfusion induced by the right unilateral common carotid artery occlusion (rUCCAO). We showed that triptolide administration alleviated the demyelination, axonal injury, and oligodendrocyte loss in the mice. Triptolide also improved cognitive function in novel object recognition test and Morris water maze test. In primary oligodendrocytes following oxygen-glucose deprivation (OGD), application of triptolide (0.001-0.1 nM) exerted concentration-dependent protection. We revealed that the protective effect of triptolide resulted from its inhibition of oligodendrocyte apoptosis via increasing the phosphorylation of the Src/Akt/GSK3β pathway. Moreover, triptolide suppressed microglial activation and proinflammatory cytokines expression after chronic cerebral hypoperfusion in mice and in BV2 microglial cells following OGD, which also contributing to its alleviation of white matter injury. Importantly, mice received triptolide at the dose of 20 μg·kg·d did not show hepatotoxicity and nephrotoxicity even after chronic treatment. Thus, our results highlight that triptolide alleviates whiter matter injury induced by chronic cerebral hypoperfusion through direct protection against oligodendrocyte apoptosis and indirect protection by inhibition of microglial inflammation. Triptolide may have novel indication in clinic such as the treatment of chronic cerebral hypoperfusion-induced SIVD.
脑白质损伤是慢性脑低灌注引起的皮质下缺血性血管性痴呆（SIVD）的主要病理改变。其特征是进行性脱髓鞘、少突胶质细胞凋亡和小胶质细胞激活，导致认知功能障碍。雷公藤内酯具有多种药理活性，包括抗炎、免疫抑制和抗肿瘤等。在这项研究中，我们研究了雷公藤内酯对慢性脑低灌注诱导的右颈总动脉闭塞（rUCCAO）小鼠脑白质损伤和认知功能障碍的影响。结果表明，雷公藤内酯可减轻小鼠脑白质脱髓鞘、轴突损伤和少突胶质细胞丢失。雷公藤内酯还改善了新奇物体识别试验和水迷宫试验中的认知功能。在氧葡萄糖剥夺（OGD）后的原代少突胶质细胞中，雷公藤内酯（0.001-0.1 nM）以浓度依赖性方式发挥保护作用。我们发现，雷公藤内酯通过增加Src/Akt/GSK3β通路的磷酸化，抑制少突胶质细胞凋亡，从而发挥保护作用。此外，雷公藤内酯在慢性脑低灌注后小鼠脑内和 OGD 后 BV2 小胶质细胞中抑制小胶质细胞激活和促炎细胞因子表达，也有助于减轻脑白质损伤。重要的是，即使在慢性治疗后，接受 20μg·kg·d 剂量雷公藤内酯的小鼠也没有表现出肝毒性和肾毒性。因此，我们的研究结果表明，雷公藤内酯通过直接保护少突胶质细胞凋亡和间接抑制小胶质细胞炎症来减轻慢性脑低灌注引起的脑白质损伤。雷公藤内酯可能在临床中具有新的应用，如治疗慢性脑低灌注引起的 SIVD。
