Low‐Intensity Pulsed Ultrasound Attenuates Neuroinflammation and Preserves Synaptic Integrity by Modulating Microglial Polarization Through the <scp>MAPK</scp> – <scp>NF</scp> ‐ <scp>κB</scp> Pathway After Traumatic Brain Injury

Traumatic brain injury (TBI) triggers a pronounced inflammatory response in the central nervous system that significantly contributes to secondary damage and long-term neurological deficits. Microglia, the resident immune cells of the brain, are key mediators of this response; however, their activation after TBI often shifts toward a proinflammatory (M1) phenotype, exacerbating tissue injury and impairing repair. This study investigated (1) the therapeutic potential of low-intensity pulsed ultrasound (LIPUS) in modulating microglial activation and polarization, and (2) its effects on inflammatory pathways, cytokine release, synaptic integrity, and functional recovery after TBI in mice. Using BV2 and primary microglia as in vitro models, we further examined the effects of LIPUS on inflammatory responses and key signaling pathways in interferon-gamma (IFN-γ)-induced microglial activation. In a controlled cortical impact mouse model, LIPUS significantly reduced microglial activation and neuroinflammation, decreased M1 polarization (CD16) while enhancing M2 polarization (CD206), preserved hippocampal synaptic integrity, and improved long-term neurological and cognitive outcomes, even when administered up to 6 h post-injury. In vitro, LIPUS attenuated IFN-γ-induced microglial activation, suppressed proinflammatory cytokine release, and inhibited activation of the mitogen-activated protein kinase-nuclear factor-κB pathway. Together, these findings demonstrate that LIPUS promotes a reparative microglial phenotype, maintains synaptic and neuronal function, and facilitates recovery after TBI, supporting its potential as a noninvasive therapeutic strategy with translational relevance.