Dexmedetomidine Ameliorates Postoperative Cognitive Dysfunction via the MicroRNA-381-Mediated EGR1/p53 Axis

Postoperative cognitive dysfunction (POCD; cognitive change associated with anesthesia and surgery) is one of the most serious long-term postoperative complications that occur in elderly patients. Dexmedetomidine (DEX) has been shown to be beneficial for improving outcomes of postoperative cognitive function. However, the exact mechanism underlying this role requires is yet to be found. The present study aims to determine the pathways involved in the protective effects of DEX against POCD in C57BL/6 J aged mice. DEX was administered after POCD modeling in C57BL/6 J aged mice. The cognitive function was evaluated after DEX treatment using novel object recognition, open field, and Y-maze tests. We also assessed its effects on neuron apoptosis and production of TNF-alpha and IL-1 beta in mouse brain tissues as well as expression levels of DNA damage-related proteins p53, p21, and gamma H2AX. Interactions between early growth response 1 (EGR1) and p53, microRNA (miR)-381, and EGR1 were identified by ChIP and luciferase reporter assays, and gain- and loss-of-function experiments were performed to confirm the involvement of their interaction in POCD. DEX administration attenuated hippocampal neuron apoptosis, neuroinflammation, DNA damage, and cognitive impairment in aged mice. miR-381 targeted EGR1 and disrupted its interaction with p53, leading to a decline in hippocampal neuron apoptosis, DNA damage, neuroinflammation, and cognitive impairment. Furthermore, DEX administration resulted in the enhancement of miR-381 expression and the subsequent inhibition of EGR1/p53 to protect against cognitive impairment in aged mice. Overall, these results indicate that DEX may have a potential neuroprotective effect against POCD via the miR-381/EGR1/p53 signaling, shedding light on the mechanisms involved in neuroprotection in POCD.