Methylene blue attenuates neuroinflammation after subarachnoid hemorrhage in rats through the Akt/GSK-3 beta/MEF2D signaling pathway
Methylene blue attenuates neuroinflammation after subarachnoid hemorrhage in rats through the Akt/GSK-3 beta/MEF2D signaling pathway
复制标题
亚甲蓝通过 Akt/GSK-3 beta/MEF2D 信号通路减轻大鼠蛛网膜下腔出血后的神经炎症
DOI：
10.1016/j.bbi.2017.04.020
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发表时间：
2017
影响因子：
15.1
通讯作者：
Chen Gao
中科院分区：
文献类型：
--
作者：
Xu Hangzhe;Li Jianru;Wang Zhijiang;Feng Majing;Shen Yongfeng;Cao Shenglong;Li Tao;Peng Yucong;Fan Linfeng;Chen Jingyin;Gu Chi;Yan Feng;Wang Lin;Chen Gao
蛛网膜下腔出血（SAH）是一个严重的医学问题，有效的药物治疗很少，神经炎症已被确定为SAH后早期脑损伤（EBI）的重要病理过程。亚甲蓝（MB）是一种较老的药物，最近被证明在几种脑损伤中发挥非凡的神经保护作用。然而，尚无研究报道MB对SAH的有益影响。在目前的研究中，我们研究了MB在SAH后EBI中的神经保护作用，并重点关注其抗炎作用。共303只大鼠进行血管内穿孔过程，以产生SAH模型。我们发现MB可以显著改善SAH后BBB破坏继发的脑水肿和神经功能障碍。MB给药还促进Akt和GSK-3β的磷酸化，导致细胞核中MEF 2D浓度增加。MB给药后细胞因子IL-10表达上调，IL-1β、IL-6和TNF-α表达下调。MB给药还可以减轻SAH后中性粒细胞浸润和小胶质细胞活化。Akt选择性抑制剂MK 2206可阻断MB的神经保护作用，抑制Akt的磷酸化，阻止MEF 2D的核定位。MK 2206还降低IL-10的表达，并增加促炎细胞因子的表达。提示MB可改善SAH后神经炎症反应，其抗炎作用可能通过激活Akt/GSK-3β/MEF 2D通路发挥。
Subarachnoid hemorrhage (SAH) is a serious medical problem with few effective pharmacotherapies available, and neuroinflammation has been identified as an important pathological process in early brain injury (EBI) after SAH. Methylene blue (MB) is an older drug that has been recently proven to exert extraordinary neuroprotective effects in several brain insults. However, no study has reported the beneficial effects of MB in SAH. In the current investigation, we studied the neuroprotective effects of MB in EBI after SAH and focused on its anti-inflammatory role. A total of 303 rats were subjected to an endovascular perforation process to produce an SAH model. We found that MB could significantly ameliorate brain edema secondary to BBB disruption and alleviate neurological dysfunction after SAH. MB administration also promoted the phosphorylation of Akt and GSK-3β, leading to an increased concentration of MEF2D in the nucleus. The cytokine IL-10 was up-regulated, and IL-1β, IL-6 and TNF-α were down-regulated after MB administration. MB administration could also alleviate neutrophil infiltration and microglia activation after SAH. MK2206, a selective inhibitor of Akt, abolished the neuroprotective effects of MB, inhibited the phosphorylation of Akt and prevented the nuclear localization of MEF2D. MK2206 also reduced the expression of IL-10 and increased the expression of pro-inflammatory cytokines. In conclusion, these data suggested that MB could ameliorate neuroinflammatory responses after SAH, and its anti-inflammatory effects might be exerted via activation of the Akt/GSK-3β/MEF2D pathway.