Neuroprotective Effects Against Cerebral Ischemic Injury Exerted by Dexmedetomidine via the HDAC5/NPAS4/MDM2/PSD-95 Axis.

Numerous evidences have highlighted the efficient role of dexmedetomidine (DEX) in multi-organ protection. In the present study, the neuroprotective role of DEX on cerebral ischemic injury and the underlining signaling mechanisms were explored. In order to simulate cerebral ischemic injury, we performed middle cerebral artery occlusion in mice and oxygen-glucose deprivation in neurons. Immunohistochemistry, Western blot analysis, and RT-qPCR were used to examine expression of HDAC5, NPAS4, MDM2, and PSD-95 in hippocampus tissues of MCAO mice and OGD-treated neurons. MCAO mice received treatment with DEX and sh-PSD-95, followed by neurological function evaluation, behavioral test, infarct volume detection by TTC staining, and apoptosis by TUNEL staining. Additionally, gain- and loss-of-function approaches were conducted in OGD-treated neuron after DEX treatment. Cell viability and apoptosis were assessed with the application of CCK-8 and flow cytometry. The interaction between MDM2 and PSD-95 was evaluated using Co-IP assay, followed by ubiquitination of PSD-95 detection. As per the results, HDAC5 and MDM2 were abundantly expressed, while NPAS4 and PSD-95 were poorly expressed in hippocampus tissues of MCAO mice and OGD-treated neurons. DEX elevated viability, and reduced LDH leakage rate and apoptosis rate of OGD-treated neurons, which was reversed following the overexpression of HDAC5. Moreover, HDAC5 augmented MDM2 expression via NPAS4 inhibition. MDM2 induced PSD-95 ubiquitination and degradation. In MCAO mice, DEX improved neurological function and behaviors and decreased infarct volume and apoptosis, which was negated as a result of PSD-95 silencing. DEX plays a neuroprotective role against cerebral ischemic injury by disrupting MDM2-induced PSD-95 ubiquitination and degradation via HDAC5 and NPAS4.