Suppressing TLR4 alleviates cerebral injury in heatstroke rats through the modulation of microglial polarization.

Objective: This study aims to explore the neuroprotective effects of inhibiting TLR4 on brain damage resulting from heatstroke (HS) and to clarify the underlying molecular mechanisms involved.

Methods: In this study, we successfully established a HS rat model. The TLR4 antagonist TAK-242 was administered to evaluate its impact on neurological dysfunction, brain edema, learning and memory deficits, and histopathological alterations in the hippocampus.

Results: The inhibition of TLR4 using TAK-242 led to a significant reduction in neurological dysfunction and brain edema in rats subjected to HS. Additionally, TAK-242 improved learning and memory impairments associated with HS and alleviated histopathological changes observed in the hippocampus. The treatment also resulted in a decrease in CD68-positive microglia and reduced expression levels of iNOS and TNF-α, while increasing CD206-positive cells and the expression of Arg-1 and IL-10. Furthermore, TAK-242 effectively reversed the elevated protein levels of TLR4, MyD88, and NF-κB induced by HS.

Conclusion: These findings indicate that TLR4 inhibition through TAK-242 may be a promising therapeutic strategy for neuroprotection in HS by modulating microglial polarization.