Melatonin alleviates secondary brain damage and neurobehavioral dysfunction after experimental subarachnoid hemorrhage: possible involvement of TLR4‐mediated inflammatory pathway
Melatonin alleviates secondary brain damage and neurobehavioral dysfunction after experimental subarachnoid hemorrhage: possible involvement of TLR4‐mediated inflammatory pathway
复制标题
DOI：
10.1111/jpi.12087
复制
发表时间：
2013-11
影响因子：
10.3
通讯作者：
Zhong Wang;Lingyun Wu;Wanchun You;C. Ji;Gang Chen
中科院分区：
文献类型：
--
作者：
Zhong Wang;Lingyun Wu;Wanchun You;C. Ji;Gang Chen
已有研究证实褪黑素通过调节氧化应激对实验性蛛网膜下腔出血（subarachnoid hemorrhage，SAH）后继发性脑损伤具有保护作用，但其对SAH模型炎症通路和继发性认知功能障碍的影响尚未见报道。本研究旨在评价褪黑激素对SAH后Toll样受体4（TLR 4）信号通路和神经行为测试的影响。成年SD大鼠随机分为4组：对照组（n = 20）、SAH组（n = 20）、SAH+溶媒组（n = 20）、SAH+褪黑素组（n = 20）。大鼠SAH模型采用视交叉前池注入新鲜动脉血0.3mL，20 s内完成。在SAH+褪黑素组中，在SAH诱导后2和24小时，以150 mg/kg腹腔注射褪黑素。在Morris水迷宫中研究认知和记忆的变化。褪黑素治疗显著降低了TLR 4通路相关因子的表达，如高迁移率族蛋白1（HMGB 1）、TLR 4、核因子-κB（NF-κB）、髓样分化因子88（MyD 88）、白细胞介素-1 β（IL-1β）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和诱导型一氧化氮合酶（iNOS）。在这个视交叉前血液注射模型中，SAH后给予褪黑激素显著改善了空间学习和记忆缺陷。凋亡和坏死的染色表明，与SAH+媒介物组相比，褪黑素治疗组中出现较少的阳性细胞。总之，褪黑激素可以减轻该SAH模型中的神经行为功能障碍，褪黑激素在实验性SAH后不仅通过抗氧化途径而且通过抗炎信号传导表现出神经保护作用。
Previous studies proved that melatonin protected against secondary brain damage by modulating oxidative stress after experimental subarachnoid hemorrhage (SAH), but it has not been evaluated yet about its effects on inflammatory pathway and secondary cognitive dysfunction in SAH model. This study was undertaken to evaluate the influence of melatonin on toll‐like receptor 4 (TLR4) signaling pathway and neurobehavioral tests after SAH. Adult SD rats were divided into four groups: control group (n = 20), SAH group (n = 20), SAH+vehicle group (n = 20), and SAH+melatonin group (n = 20). The rat SAH model was induced by injection of 0.3 mL fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20 s. In SAH+melatonin group, melatonin was administered i.p. at 150 mg/kg at 2 and 24 hr after the induction of SAH. Cognitive and memory changes were investigated in the Morris water maze. Treatment with melatonin markedly decreased the expressions of TLR4 pathway‐related agents, such as high‐mobility group box 1 (HMGB1), TLR4, nuclear factor‐κB (NF‐κB), myeloid differentiation factor 88 (MyD88), interleukin‐1β (IL‐1β), tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and inducible nitric oxide synthase (iNOS). Administration of melatonin following SAH significantly ameliorated spatial learning and memory deficits in this prechiasmatic blood injection model. Staining of apoptosis and necrosis indicated that fewer positive cells appeared in melatonin‐treated group than SAH+vehicle group. In conclusion, melatonin may attenuate neurobehavioral dysfunction in this SAH model, and melatonin exhibits neuroprotection possibly not only through anti‐oxidative pathway but also anti‐inflammatory signaling after experimental SAH.