Neuroprotective Effects of Transcranial Pulsed Current Stimulation: Modulation of Microglial Polarization in Traumatic Brain Injury

ABSTRACT Objective Traumatic brain injury (TBI), a prevalent neurological disorder worldwide, is marked by varying degrees of neurological dysfunction. A key contributor to secondary damage and impediments in the repair process is the unregulated activation of microglia, which triggers neuroinflammation. Emerging evidence highlights the therapeutic potential of transcranial pulsed current stimulation (tPCS) in mitigating neurological deficits. However, despite these promising neuroprotective effects, its role and exact mechanisms in TBI remain unclear. Methods Herein, a mouse model of TBI was established, and daily 30‐min tPCS treatments were administered for five consecutive days. Subsequently, we conducted comprehensive assessments of neurological function, microglial activation status, and neuroplasticity in the treated subjects. Additionally, a co‐culture system of BV2 and HT22 cells was developed, using LPS to activate microglia, to explore potential neuroprotective mechanisms. Results Our findings revealed that tPCS plays a crucial role in mitigating neuroinflammation and promoting neurological recovery following TBI. The underlying mechanism likely involves tPCS enhancing orexin‐A (OX‐A) expression, which subsequently suppresses the NF‐κB pathway and promotes the expression of neurorepair‐related markers. In vitro experiments further clarified these findings, demonstrating that OX‐A effectively inhibited LPS‐induced M1 microglial polarization and promoted a shift towards the M2 phenotype. Furthermore, OX‐A significantly reduced intracellular ROS production and microglia‐induced neuronal apoptosis. Conclusion These findings indicate that tPCS regulates microglial phenotype via the OX‐A/NF‐κB pathway, thereby suppressing neuroinflammation and enhancing neuroplasticity. These results provide a new perspective for the rehabilitation of individuals with TBI.