Abstract: Traumatic brain injury can be categorized into primary and secondary injuries. Secondary injuries are the main cause of disability following traumatic brain injury, which involves a complex multicellular cascade. Microglia play an important role in secondary injury and can be activated in response to traumatic brain injury. In this article, we review the origin and classification of microglia as well as the dynamic changes of microglia in traumatic brain injury. We also clarify the microglial polarization pathways and the therapeutic drugs targeting activated microglia. We found that regulating the signaling pathways involved in pro-inflammatory and anti-inflammatory microglia, such as the Toll-like receptor 4 /nuclear factor-kappa B, mitogen-activated protein kinase, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/protein kinase B, Notch, and high mobility group box 1 pathways, can alleviate the inflammatory response triggered by microglia in traumatic brain injury, thereby exerting neuroprotective effects. We also reviewed the strategies developed on the basis of these pathways, such as drug and cell replacement therapies. Drugs that modulate inflammatory factors, such as rosuvastatin, have been shown to promote the polarization of antiinflammatory microglia and reduce the inflammatory response caused by traumatic brain injury. Mesenchymal stem cells possess anti-inflammatory properties, and clinical studies have confirmed their significant efficacy and safety in patients with traumatic brain injury. Additionally, advancements in mesenchymal stem cell-delivery methods—such as combinations of novel biomaterials, genetic engineering, and mesenchymal stem cell exosome therapy—have greatly enhanced the efficiency and therapeutic effects of mesenchymal stem cells in animal models. However, numerous challenges in the application of drug and mesenchymal stem cell treatment strategies remain to be addressed. In the future, new technologies, such as single-cell RNA sequencing and transcriptome analysis, can facilitate further experimental studies. Moreover, research involving non-human primates can help translate these treatment strategies to clinical practice.

Key words: animal model, anti-inflammatory drug, cell replacement strategy, central nervous system, mesenchymal stem cell, microglia, neuroinflammation, non-human primate, signaling pathway, traumatic brain injury