Resatorvid Modulates Microglial M1/M2 Polarization to Improve Cognitive Impairment after Repetitive Mild Traumatic Brain Injury

Abstract Background In recent years, more and more attention has been paid to repetitive mild TBI (rmTBI), which can increase the incidence of chronic neurodegenerative disorders. Microglia are the main mediators of the innate immune response in the central nervous system (CNS), and their polarization phenotype plays a dual role in exerting beneficial and detrimental effects on neuroinflammation. This study investigated the mechanism and effect of Resatorvid (TAK242), a specific inhibitor of TLR4, on learning and memory in mice with rmTBI. Methods A controlled cortical impact (CCI) method was used to establish the mild TBI model in this study. Mice in the rmTBI model underwent four head impacts with a 24-hour interval between each impact. Results TAK242 treatment significantly reduced the expression levels of APP and p-Tau, promoted neurological recovery, and improved learning and memory after rmTBI. Furthermore, TAK242 promoted the polarization of microglia from the M1 to M2 phenotype, accompanied by the upregulation of anti-inflammatory factors and downregulation of pro-inflammatory factors. The inhibition of the TLR4/MyD88/NF-κB signalling pathway might be involved in the protective effect of TAK242 mentioned above. Conclusions TAK242 significantly inhibits the neuroinflammatory response by regulating microglial M1/M2 polarization, thereby improving cognitive function after rmTBI.