Enhancing glymphatic transport through angiotensin II type 2 receptor activation promotes neurological recovery after traumatic brain injury

<b>Background:</b> Traumatic brain injury (TBI) may impair the function of the glymphatic system, leading to diminished metabolic waste clearance and aggravated neurological deficits. While angiotensin II type 2 receptor (AT2R) activation has demonstrated neuroprotective effects, its specific impact on the glymphatic system following TBI remains uncharacterized. <b>Methods:</b> We utilized near-infrared II (NIR-II) probes with distinct protein-binding capacities to visualize glymphatic transport in TBI mice and investigate how compound 21 (C21)-mediated AT2R activation modulates post-traumatic glymphatic function. Perivascular aquaporin-4 (AQP4) polarization was analyzed by immunofluorescence. RNA sequencing was performed to explore the C21-induced dynamic immune modulation. β-amyloid clearance efficiency and phosphorylated tau accumulation were quantified in mouse brain tissue. Motor and cognitive functions were comprehensively evaluated through standardized behavioral tests. <b>Results:</b> Our results demonstrate that C21-mediated AT2R activation enhanced glymphatic influx and promoted glymphatic clearance after TBI. Mechanistically, AT2R activation restored perivascular aquaporin-4 (AQP4) polarization and cerebral blood flow, suppressed astrogliosis and microglial activation, and attenuated neuroinflammatory responses. Furthermore, AT2R activation enhanced β-amyloid clearance efficiency and reduced phosphorylated tau accumulation, thereby promoting motor and cognitive functional recovery. <b>Conclusion:</b> By employing non-invasive or minimally invasive NIR-II imaging, our study highlights the protective effects of AT2R activation on the glymphatic system following TBI, revealing its potential as a promising therapeutic strategy for mitigating TBI-induced damage and improving neurological outcomes.