Nr1d1 Regulates Microglia M1/M2 Polarization to Alleviate Neuroinflammation after Traumatic Brain Injury

Microglia-mediated neuroinflammation constitutes a pivotal secondary injury mechanism after traumatic brain injury (TBI). Recent studies have unveiled the role of <i>Nr1d1</i> in neuroinflammation and glial activation in the Central Nervous System (CNS) injury, found the activation of <i>Nr1d1</i> appears to prevent inflammation and apoptosis cell death. However, the role of <i>Nr1d1</i> in the regulation of M1/M2 polarization and neuroinflammatory responses in TBI remains unclear. The purpose of this study is to investigate the effects of <i>Nr1d1</i> on neuroinflammatory responses in the acute phase of TBI. SR9009 (100 mg/kg) was administered by intraperitoneal injection to activate <i>Nr1d1.</i> Neurological impairments were assessed using the modified neurological severity score (mNSS). Molecular levels were evaluated through Western Blotting and quantitative real-time polymerase chain reaction. Measurement of the water content of brain tissue was used to assess cerebral edema, and the damaged area of brain tissue was evaluated by Hematoxylin-Eosin (H&E) staining. The functional behavioral assessment was used to evaluate the cognitive impairments and emotional change. Our study, for the first time, demonstrates that the circadian rhythm of <i>Nr1d1</i> is disrupted during the acute phase of TBI. We also found Nr1d1 prevented nerve dysfunction and contributed to the recovery of neurological impairment, promoted the transformation of microglia phenotype, and reduced the damage to neurons, synaptic structures, and the neuroinflammation. These findings unveiled that <i>Nr1d1</i> may represent a promising therapeutic target for the successful treatment of TBI and for improving neurological deficits during the acute phase of TBI.