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.
Keywords: Cognitive dysfunction; Intestinal ischemia reperfusion; Melatonin; Microglia; Neuroinflammation; TLR4.
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