Inhibition of Toll-like receptor 4 (TLR4)-mediated inflammatory pathways exerts a critical effect on neuronal death; therefore, it is a possible new therapeutic approach for traumatic brain injury (TBI). Resatorvid (TAK-242) is a novel small-molecule compound widely used to inhibit TLR4-mediated pathways, but the protective mechanism of TAK-242 in TBI remains unclear. Herein, we analyzed the neuroprotective effects of TAK-242 in rats after TBI. The rat model of brain injury was established using a modified Free-fall device, and the rats were injected with TAK-242 (0.5 mg/kg) through the caudal vein before TBI. The rats were allocated into four groups: a sham group, a TBI group, a TBI + vehicle group, and a TBI + TAK-242 group. The brain tissue was extracted for histology and determination of the expression of autophagy-related proteins and inflammatory mediators. TAK-242 pretreatment significantly reduced the damage to hippocampal neurons. Neuronal autophagy increased after brain injury, whereas TAK-242 significantly reduced autophagy marker protein LC3-II in the hippocampus. In addition, TAK-242 pretreatment significantly downregulated NF-κB p65, TNF-α, and IL-1β in the hippocampus. In conclusion, TAK-242 significantly reduced hippocampal neuronal damage by inhibiting autophagy and neuroinflammatory activity, possibly via the NF-κB signaling pathway.
Keywords: TAK-242; autophagy; neuroinflammation; toll-like receptor 4; traumatic brain injury.
© 2023 the author(s), published by De Gruyter.