Dexmedetomidine inhibits the PSD95-NMDA receptor interaction to promote functional recovery following traumatic brain injury.

The present study examined the effects of dexmedetomidine (Dex) on cognitive and motor recovery in mice following traumatic brain injury (TBI). TBI induces synaptic damage, which leads to motor dysfunction and cognitive decline. Although Dex is known to induce neuroprotection, its role following TBI remains unknown. In the present study, male C57BL/6 mice (8 weeks old; n=72) were subjected to cortical impact injury to generate a TBI mice model. Mice were divided into four groups: TBI, sham, TBI + vehicle, and TBI + Dex. Mice in the TBI + vehicle and TBI + Dex groups received intraperitoneal injections of saline (n=18) and 100 µg/kg Dex (n=18), respectively, at 1 and 12 h following surgery. At 24 h post-injury, 10 animals from each group were sacrificed, and brain tissue was isolated for Fluoro-Jade B staining and RNA and protein extraction. At 72 h post-TBI, motor function was evaluated. Furthermore, cognitive impairment was assessed between day 14 and 19 using the Morris water maze. The results demonstrated that the mRNA and protein expression of post-synaptic density 95 (PSD95) was reduced post-TBI. In addition, neuronal degeneration was evaluated using FJB staining, where PSD95 formed a complex with the N-methyl-D-aspartic acid (NMDA) receptor subunit (NR2B) and neuronal nitric oxide synthase (nNOS) inducing neuronal death post-TBI. Treatment with Dex efficiently decreased the PSD95-NR2B-nNOS interaction, which reduced the TBI-induced neuronal death. Furthermore, Dex treatment contributed to the enhanced cognitive and motor recovery following TBI. The results from the present study reported a potential mechanistic action of Dex treatment post-TBI, which may be associated with the inhibition of PSD95-NMDA interaction.