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

Abstract

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.

Comparing the Effect of Dexmedetomidine and Midazolam in Patients with Brain Injury

“…In Zhao’s study, they found that post-synaptic density 95 (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. After administering dexmedetomidine, the PSD95–NR2B–nNOS interaction was decreased efficiently, and they found dexmedetomidine could enhance cognitive and motor recovery following TBI [ 9 ]. Another study showed that dexmedetomidine can alleviate cerebral ischemic reperfusion injury in rats by increasing the α2-adrenergic receptor and blocking JNK phosphorylation and the activation of caspase-3 [ 10 ].…”

“…As a highly selective central agonist of the α2 adrenergic receptor, dexmedetomidine has been administered in many therapeutic procedures safely and efficiently [ 6 , 7 , 8 ]. Animal studies showed that dexmedetomidine reduced neuronal death by protecting against neural autophagy and neuroinflammation, enhanced cognitive and motor recovery following traumatic brain injury, and alleviated cerebral ischemic reperfusion injury [ 9 , 10 , 11 ]. Hence, dexmedetomidine was recommended in patients after craniotomy in recent years [ 12 , 13 , 14 , 15 , 16 ].…”

The neuroprotective effect of dexmedetomidine and its mechanism

“…Huang and Lia et al suggested that DEX could reduce the apoptosis of nerve cells in patients with brain injury caused by oxidative stress through the proliferator-activated receptorgamma coactivator 1α (PGC-1α) pathway, and DEX decreased MDA levels while increasing SOD and GPX levels (Xu et al, 2014;Huang and Jiang, 2019). Zhao et al (2021) showed that the expression of postsynaptic density protein 95 (PSD95) was decreased in TBI mouse brain tissues, while the levels of the PSD95-N-methyl-D-aspartic acid (PSD95-NMDA) complex were significantly increased. Excessive levels of the PSD95-NMDA complex can lead to the massive release of NO and activate matrix metallopeptidase 9 (MMP9), thus inducing apoptosis, and DEX can inhibit the formation of the PSD95-NMDA complex.…”

Effect Evaluation of Dexmedetomidine Intravenous Anesthesia on Postoperative Agitation in Patients with Craniocerebral Injury by Magnetic Resonance Imaging Based on Sparse Reconstruction Algorithm

“…However, the CT scan cannot detect the skull base, posterior fossa, and non-hemorrhagic injuries [ 7 ]. Due to its inability to examine shear injuries of white matter, corpus callosum, and brainstem, the CT scan has little help in the examination of the patients with severe illness and does not show substantial advantages in the long-term prognosis [ 8 ]. With the continuous development and progress of imaging technology, magnetic resonance imaging (MRI) has been rapidly developed, which provides the reference and basis for the diagnosis of craniocerebral injury.…”