Abstract：
BACKGROUND: Neuroinflammation following peripheral surgery plays a key role in postoperative cognitive dysfunction (POCD) development and there is no effective therapy to inflammation-mediated cognitive impairment. Recent studies showed that rutin, a natural flavonoid compound, conferred neuroprotection. However, the effects and mechanisms of rutin on cognition of surgical and aged mice and LPS-induced BV2 need deeper exploration.
METHODS: The effect of rutin in vivo and vitro were evaluated by Morris water maze test, HE stainin, Golgi-Cox staining, IF, IHC, RT-PCR, Flow Cytometer and Western blotting. In vivo, aged mice were treated with rutin and surgery. In vitro, rutin, Nrf2 knockdown, MAC-1 overexpression and VX765, a caspase-1 inhibitor, were administration on BV2 microglial cells.
RESULTS: Surgery led to compensatory increase in nuclear Nrf2 and rutin could further increase it. Neural damage was accompanied with high level in MAC-1, caspase-1-mediated pyroptosis and M1 microglia, while rutin recovered the process. Nrf2 inhibition abolished the effect of rutin with the increase of MAC-1, caspase-1-mediated pyroptosis and M1 microglia. Activation of MAC-1 abrogated protection of rutin by increase in pyroptosis and M1 microglia. Finally, we found that treatment with VX765 improved injury and increased M2 microglia against overexpression of MAC-1.
CONCLUSIONS: Our study indicated that rutin may be a potential therapy in POCD and exerted neural protection via Nrf2/ Mac-1/ caspase-1-mediated inflammasome axis to regulate pyroptosis and microglial polarization.
METHODS: The effect of rutin in vivo and vitro were evaluated by Morris water maze test, HE stainin, Golgi-Cox staining, IF, IHC, RT-PCR, Flow Cytometer and Western blotting. In vivo, aged mice were treated with rutin and surgery. In vitro, rutin, Nrf2 knockdown, MAC-1 overexpression and VX765, a caspase-1 inhibitor, were administration on BV2 microglial cells.
RESULTS: Surgery led to compensatory increase in nuclear Nrf2 and rutin could further increase it. Neural damage was accompanied with high level in MAC-1, caspase-1-mediated pyroptosis and M1 microglia, while rutin recovered the process. Nrf2 inhibition abolished the effect of rutin with the increase of MAC-1, caspase-1-mediated pyroptosis and M1 microglia. Activation of MAC-1 abrogated protection of rutin by increase in pyroptosis and M1 microglia. Finally, we found that treatment with VX765 improved injury and increased M2 microglia against overexpression of MAC-1.
CONCLUSIONS: Our study indicated that rutin may be a potential therapy in POCD and exerted neural protection via Nrf2/ Mac-1/ caspase-1-mediated inflammasome axis to regulate pyroptosis and microglial polarization.
摘要：
背景：外周手术后的神经炎症在术后认知功能障碍（POCD）的发展中起着关键作用，目前尚无有效的治疗炎症介导的认知障碍的方法。最近的研究表明，芦丁，一种天然的黄酮类化合物，赋予神经保护。然而,芦丁对手术、老年小鼠认知功能及LPS诱导的BV2的影响及机制有待进一步探讨。
方法：通过Morris水迷宫试验评价芦丁的体内外作用，他染色素，高尔基-考克斯染色,如果,IHC,RT-PCR,流式细胞仪和Western印迹。在体内,老年小鼠接受芦丁和手术治疗。体外，芦丁,Nrf2击倒，MAC-1过表达和VX765，一种caspase-1抑制剂，在BV2小胶质细胞上施用。
结果：手术导致核Nrf2的代偿性增加，芦丁可以进一步增加它。神经损伤伴随着高水平的MAC-1，caspase-1介导的焦凋亡和M1小胶质细胞，而鲁丁恢复了这个过程。Nrf2抑制随着MAC-1，caspase-1介导的焦亡和M1小胶质细胞的增加而消除了芦丁的作用。MAC-1的激活通过增加焦亡和M1小胶质细胞来消除芦丁的保护。最后,我们发现用VX765治疗可改善损伤,并增加M2小胶质细胞对抗MAC-1过表达.
结论：我们的研究表明芦丁可能是POCD的潜在治疗方法，并通过Nrf2/Mac-1/caspase-1介导的炎症小体轴发挥神经保护作用，以调节细胞凋亡和小胶质细胞极化。
方法：通过Morris水迷宫试验评价芦丁的体内外作用，他染色素，高尔基-考克斯染色,如果,IHC,RT-PCR,流式细胞仪和Western印迹。在体内,老年小鼠接受芦丁和手术治疗。体外，芦丁,Nrf2击倒，MAC-1过表达和VX765，一种caspase-1抑制剂，在BV2小胶质细胞上施用。
结果：手术导致核Nrf2的代偿性增加，芦丁可以进一步增加它。神经损伤伴随着高水平的MAC-1，caspase-1介导的焦凋亡和M1小胶质细胞，而鲁丁恢复了这个过程。Nrf2抑制随着MAC-1，caspase-1介导的焦亡和M1小胶质细胞的增加而消除了芦丁的作用。MAC-1的激活通过增加焦亡和M1小胶质细胞来消除芦丁的保护。最后,我们发现用VX765治疗可改善损伤,并增加M2小胶质细胞对抗MAC-1过表达.
结论：我们的研究表明芦丁可能是POCD的潜在治疗方法，并通过Nrf2/Mac-1/caspase-1介导的炎症小体轴发挥神经保护作用，以调节细胞凋亡和小胶质细胞极化。
