Intestinal ischemia/reperfusion (I/R) can cause multiple organ damage with extremely high morbidity and mortality. Melatonin has anti-inflammatory, anti-oxidative and anti-apoptotic effects against various diseases. This study aimed to explore whether melatonin had a protective effect against intestinal I/R-induced neuroinflammation and cognitive dysfunction, and investigate its potential mechanisms. In this study, melatonin was administered to the rats with intestinal I/R, then histological changes in intestine and brain (frontal cortex and hippocampal CA1 area) tissues and cognitive function were detected, respectively. The encephaledema and blood–brain barrier (BBB) permeability were observed. Moreover, the alterations of proinflammatory factors (tumor necrosis factor-α, interleukin-6 and interleukin-1β), oxidative response (malondialdehyde, superoxide dismutase, and reactive oxygen species), apoptosis and proteins associated with inflammation, including Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and phosphorylated nuclear factor kappa beta (NF-κB), and apoptosis (cleaved caspase-3) in brain tissues were examined. Furthermore, the expressions of TLR4, Myd88, and microglial activity were observed by multiple immunofluorescence staining. The results showed that intestinal I/R-induced abnormal neurobehavior and cerebral damage were ameliorated after melatonin treatment, which were demonstrated by improved cognitive dysfunction and aggravated histology. Furthermore, melatonin decreased the levels of proinflammatory factors and oxidative stress in plasma, intestine and brain tissues, attenuated apoptotic cell, and inhibited the expressions of related proteins and the immunoreactivity of TLR4 or Myd88 in microglia in brain tissues. These findings showed that melatonin might relieve neuroinflammation and cognitive dysfunction caused by intestinal I/R, which could be, at least partially, related to the inhibition of the TLR4/Myd88 signaling in microglia.

肠缺血/再灌注（I / R）会导致多器官损伤，发病率和死亡率极高。褪黑素对各种疾病具有抗炎，抗氧化和抗凋亡作用。这项研究旨在探讨褪黑激素是否对肠道I / R引起的神经炎症和认知功能障碍具有保护作用，并探讨其潜在机制。在这项研究中，将褪黑素施用于具有肠道I / R的大鼠，然后分别检测了肠道和大脑（额叶皮层和海马CA1区）的组织学变化和认知功能。观察到脑水肿和血脑屏障（BBB）通透性。此外，促炎因子（肿瘤坏死因子-α，白介素-6和白介素-1β），氧化反应（丙二醛，超氧化物歧化酶和活性氧），凋亡和与炎症相关的蛋白，包括Toll样受体4（TLR4），髓样分化因子88（Myd88）和磷酸化核因子kappa beta（NF-κB）和凋亡（胱天蛋白酶裂解） -3）检查脑组织。此外，通过多重免疫荧光染色观察到TLR4，Myd88和小胶质细胞活性的表达。结果表明，褪黑激素治疗后肠I / R诱导的异常神经行为和脑损伤得到改善，这通过改善的认知功能障碍和恶化的组织学表现得到证明。此外，褪黑素可降低血浆，肠和脑组织中促炎因子和氧化应激的水平，减少凋亡细胞，并抑制脑组织小胶质细胞中相关蛋白的表达和TLR4或Myd88的免疫反应。这些发现表明，褪黑激素可以缓解由肠I / R引起的神经炎症和认知功能障碍，这至少部分与抑制小胶质细胞中的TLR4 / Myd88信号有关。