Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Laboratory of Anesthesiology, Southwest Medical University, Luzhou, China.
Oxid Med Cell Longev. 2022 Aug 18;2022:8729398. doi: 10.1155/2022/8729398. eCollection 2022.
Cerebral ischemia/reperfusion (I/R) injury is a clinical event associated with high morbidity and mortality. Neuroinflammation plays a crucial role in the pathogenesis of I/R-induced brain injury and cognitive decline. Low-density lipoprotein receptor-related protein-1 (LRP1) can exert strong neuroprotection in experimental intracerebral hemorrhage. However, whether LRP1 can confer neuroprotective effects after cerebral I/R is yet to be elucidated. The present study is aimed at investigating the effects of LRP1 activation on cerebral I/R injury and deducing the underlying mechanism involving TXNIP/NLRP3 signaling pathway. Cerebral I/R injury was induced in mice by bilateral common carotid artery occlusion. LPR1 ligand, apoE-mimic peptide COG1410, was administered intraperitoneally. To elucidate the underlying mechanism, overexpression of TXNIP was achieved via the hippocampal injection of AAV-TXNIP before COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, Western blot, enzyme-linked immunosorbent assay, HE, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. Our results showed that the expressions of endogenous LRP1, TXNIP, NLRP3, procaspase-1, and cleaved caspase-1 were increased after cerebral I/R. COG1410 significantly ameliorated cerebral I/R-induced neurobehavioral deficits, brain edema, histopathological damage, and poor survival rate. Interestingly, COG1410 inhibited microglia proinflammatory polarization and promoted anti-inflammatory polarization, decreased oxidative stress, attenuated apoptosis, and inhibited the expression of the TXNIP/NLRP3 signaling pathway. However, the benefits of COG1410 were abolished by TXNIP overexpression. Thus, our study suggested that LRP1 activation with COG1410 attenuated cerebral I/R injury at least partially related to modulating microglial polarization through TXNIP/NLRP3 signaling pathway in mice. Thus, COG1410 treatment might serve as a promising therapeutic approach in the management of cerebral I/R patients.
脑缺血/再灌注（I/R）损伤是一种与高发病率和死亡率相关的临床事件。神经炎症在 I/R 诱导的脑损伤和认知能力下降的发病机制中起着关键作用。低密度脂蛋白受体相关蛋白-1（LRP1）在实验性脑出血中具有很强的神经保护作用。然而，LRP1 是否能在脑 I/R 后发挥神经保护作用仍有待阐明。本研究旨在探讨 LRP1 激活对脑 I/R 损伤的影响，并推断其涉及 TXNIP/NLRP3 信号通路的潜在机制。通过双侧颈总动脉闭塞法诱导小鼠脑 I/R 损伤。LRP1 配体 apoE 模拟肽 COG1410 经腹腔给药。为了阐明潜在机制，在 COG1410 治疗前通过海马注射 AAV-TXNIP 实现 TXNIP 的过表达。进行神经行为学测试、脑水含量、免疫荧光、Western blot、酶联免疫吸附试验、HE 和末端脱氧核苷酸转移酶 dUTP 缺口末端标记染色。我们的结果表明，脑 I/R 后内源性 LRP1、TXNIP、NLRP3、procaspase-1 和 cleaved caspase-1 的表达增加。COG1410 显著改善脑 I/R 诱导的神经行为缺陷、脑水肿、组织病理学损伤和低存活率。有趣的是，COG1410 抑制小胶质细胞促炎极化并促进抗炎极化，减少氧化应激，减弱细胞凋亡，并抑制 TXNIP/NLRP3 信号通路的表达。然而，COG1410 的益处被 TXNIP 的过表达所消除。因此，我们的研究表明，用 COG1410 激活 LRP1 可减轻至少部分与通过 TXNIP/NLRP3 信号通路调节小胶质细胞极化相关的小鼠脑 I/R 损伤。因此，COG1410 治疗可能成为治疗脑 I/R 患者的一种有前途的方法。
