Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, People's Republic of China.
Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, People's Republic of China.
J Neuroimmune Pharmacol. 2021 Jun;16(2):306-317. doi: 10.1007/s11481-020-09911-0. Epub 2020 Apr 14.
The macrophage scavenger receptor 1 (MSR1)-induced resolution of neuroinflammation may be a novel therapeutic strategy for ischemic stroke. Our previous study showed that the neuroprotective and anti-inflammatory effects of phthalide are associated with the inhibition of the post-ischemic damage-associated molecular pattern (DAMP)/Toll-like receptor 4 (TLR4) pathway. This study investigated the effects of the phthalide derivative CD21 on ischemic brain injury and the mechanism underlying MSR1-induced resolution of neuroinflammation. Using a rat model of 2 h transient middle cerebral artery occlusion (MCAO), MSR1-induced peroxiredoxin1 (PRX1) clearance in RAW264.7 macrophages were investigated. We show here that CD21 significantly ameliorated infarct volumes and neurological deficits in a dose-dependent manner with a ≥ 12 h therapeutic time window. Moreover, administration of 5 mg/kg/day CD21 over 24 h significantly reduced pathological damages, with associated inhibition of PRX1 expression, reduced TLR4/nuclear factor-κB activation and the suppression of the inflammatory response in MCAO rats. Furthermore, the expression of MAFB/MSR1 in the ischemic brain was elevated and the phagocytosis of PRX1 in CD68-positive macrophages isolated from the ischemic brain was enhanced. Further in vitro studies show that CD21 (20 μM) strongly enhanced the Msr1 mRNA and MSR1 protein levers in RAW264.7 cells and PRX1 internalization in cellular lysosomes, which were significantly reversed by N-acetylcysteine treatment. These results suggest that CD21 may exert neuroprotective and anti-inflammatory effects with a wide time window for the treatment of ischemic stroke. The anti-stroke effects of CD21 appear to be mediated partially via the induction of MSR1-promoted DAMP (PRX1) clearance, TLR4/nuclear factor-κB pathway inhibition, and the resolution of inflammation. Graphical Abstract The neuroprotective action of CD21 was associated with the resolution of neuroinflammation through enhancement of the MAFB-MSR1 pathway that leads to DAMP (PRX1) phagocytosis and TLR4 pathway inhibition. Red solid arrows represent promotion, red dotted arrow represents the positive correlation, green arrows represent inhibition.
清道夫受体 1（MSR1）诱导的神经炎症消退可能是缺血性中风的一种新的治疗策略。我们之前的研究表明，藁本内酯的神经保护和抗炎作用与抑制缺血后损伤相关分子模式（DAMP）/Toll 样受体 4（TLR4）通路有关。本研究探讨了苯酞衍生物 CD21 对缺血性脑损伤的影响及其诱导神经炎症消退的机制。使用 2 小时短暂性大脑中动脉闭塞（MCAO）大鼠模型，研究了 MSR1 诱导 RAW264.7 巨噬细胞中过氧化物酶 1（PRX1）清除的情况。我们在这里表明，CD21 以剂量依赖性方式显著改善梗死体积和神经功能缺损，治疗时间窗≥12 小时。此外，24 小时内给予 5mg/kg/天 CD21 可显著减轻病理损伤，同时抑制 PRX1 表达，降低 TLR4/核因子-κB 激活，并抑制 MCAO 大鼠的炎症反应。此外，缺血性脑内的 MAFB/MSR1 表达升高，从缺血性脑内分离的 CD68 阳性巨噬细胞吞噬 PRX1 的能力增强。进一步的体外研究表明，CD21（20μM）可强烈增强 RAW264.7 细胞中的 Msr1 mRNA 和 MSR1 蛋白水平以及细胞溶酶体中的 PRX1 内化，这一作用可被 N-乙酰半胱氨酸处理显著逆转。这些结果表明，CD21 可能通过诱导 MSR1 促进 DAMP（PRX1）清除、TLR4/核因子-κB 通路抑制和炎症消退，在缺血性中风的治疗中发挥神经保护和抗炎作用，并具有较宽的治疗时间窗。CD21 的抗中风作用部分通过诱导 MSR1 促进 DAMP（PRX1）吞噬和 TLR4 通路抑制，以及炎症消退的 MAFB-MSR1 通路来实现。
