Deep Hypothermic Low Flow Results in Multiple Aspects of Neurological Deficits in Mice by eEF2 Hyperphosphorylation.

Postoperative neurological dysfunction is a common complication caused by deep hypothermia with cerebral hypoperfusion during aortic arch surgery, but the exact pathological changes and molecular mechanisms are not yet clear. In this study, we established an adult mouse model of deep hypothermic low flow (DHLF) to simulate the ischemic-reperfusion brain injury during aortic arch surgery. The DHLF-modeled mice showed significant neurological and cognitive dysfunction, accompanied by reduced dendritic spine density and increased glial cell activation in the hippocampus and cortex. DHLF induced proteomic changes primarily involved in synaptic organization in the hippocampus and cortex, with AMPA and NMDA receptor subunits and synaptic activity-dependent proteins markedly downregulated in the hippocampus and/or cortex. Moreover, DHLF also resulted in altered proteome in mRNA translation and inhibition of eukaryotic elongation factor 2 (eEF2), a crucial regulator of translational elongation whose activity is negatively regulated via phosphorylation by eEF2 kinase (eEF2K). Importantly, the administration of the small-molecular eEF2K inhibitor A484954 ameliorated DHLF-induced neurobehavioral dysfunction, dendritic spine reduction, and glial cell activation, suggesting that eEF2K/eEF2 may be a promising therapeutic target in DHLF-induced neurological injury. Our findings revealed new evidence of pathological features, molecular mechanism, and intervention of DHLF-induced cerebral ischemia-reperfusion injury, providing promising insight for developing strategies on reducing postoperative neurological complications after aortic arch surgery.
Competing Interests: Declarations. Ethics Approval and Consent to Participate: All animal experimental procedures were approved by the local ethical committee of Jinan University (approval no. IACUC-20220407–08). Consent for Publication: All authors have approved the content of this manuscript and provided consent for publication. Conflict of Interest: The authors declare no competing interests.
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