Abstract: Objective To investigate the mechanism of Toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) signaling pathway in exertional heat stroke (EHS) rats with brain injury. Methods Thirty SPF Sprague Dawley rats were randomly divided into control group,model group and Eritoran group,with 10 rats in each group.EHS rat models were established in the model group and Eritoran group.Eritoran (5 mg/kg) was intraperitoneally injected into the rats of Eritoran group immediately after the successful establishment of EHS model.Rats in model group were immediately intraperitoneally injected with the same amount of normal saline.The control group did not receive any treatment.The levels of serum tumor necrosis factor-ɑ(TNF-α),interleukin-1β (IL-1β) and interleukin-6 (IL-6) were detected by enzyme-linked immunosorbent assay (ELISA),HE staining was used to examine the pathological changes of brain tissues in rats,Western blotting and real-time quantitative PCR were used to detect the expression of TLR4 and nuclear factor-kappaB (NF-κB) protein and mRNA in rats' brain. Results No neuronal degeneration,edema,and infiltration of inflammatory cells was observed in the brain tissue of the control group.However,hyperemia and edema,degenerated and necrotic neuronal cells could be seen in the brain tissue of rats in the model group,and infiltrated inflammatory cells increased obviously.There was a small amount of neuronal cells with mild edema and degeneration in the brain tissue of rats in the Eritoran group,and a small amount of inflammatory cells were infiltrated.The expressions of TLR4,NF-κB protein and mRNA in the brain tissuesof rats in the model group,the Eritoran group and the control group,and the differences between the latter two groups were also significant (all P<0.05).The levels of serum TNF-α,IL-1β and IL-6 in the model group were higher than those in the Eritoran group and the control group (all P<0.05),and they were higher in the Eritoran group than those in the control group (all P<0.05). Conclusion TLR4/NF-κB signaling pathway may be involved in the occurrence and development of EHS brain injury.Inhibition of activation of this pathway is expected to be a new target for the treatment of EHS brain injury.