Dexmedetomidine Ameliorates Morris Water Maze Learning in Rats with Postoperative Cognitive Dysfunction by Enhancing Mitophagy and Inhibiting the Activation of the NLRP3 Inflammasome

Abstract

Background: Postoperative cognitive dysfunction (POCD) is an adverse event in cognitive behavior after surgery and anesthesia. Dexmedetomidine (Dex) is a central sympathetic drug that can alleviate the process of POCD by reducing the inflammatory response. However, the underlying mechanism of Dex on POCD need be further clarification. Methods: The left liver lobules of POCD rats were surgically removed to establish a model group. The Morris water maze test was used to assess the behavior of healthy Sprague Dawley (SD) rats (male, 7–8 months old) and evaluate their cognitive abilities. All the rats were anesthetized and treated with an intraperitoneal injection of 2 mL of normal saline 30 minutes before operation and 2% pentobarbital sodium during the operation. Hematoxylin-eosin staining, TUNEL (Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling) staining and immunofluorescence staining were used to assess changes in hippocampal tissue structure, cell apoptosis, microglial cell production and NLRP3 (NOD-like receptor thermal protein domain associated protein 3) expression levels, respectively. Western blot analysis of hippocampal tissue protein was used to determine the expression of NLRP3 inflammasome protein and mitophagy-related protein. An ELISA (enzyme linked immunosorbent assay) assay was used to assess changes on inflammatory factors in peripheral blood. Finally, reactive oxygen species and MDA kits were used to assess oxidative stress levels in the hippocampus. Results: It was found that Dex significantly ameliorated spatial learning and reference memory in POCD rats, attenuated neuronal injury and apoptosis in the hippocampus, and inhibited the production of microglial cells and the activity of the NLRP3 inflammasome. This process depends on PINK1 (PTEN induced putative kinase 1)/Parkin-mediated enhancement of mitophagy and a reduction of mitochondrial oxidative stress. Conclusions: Dex may promote mitochondrial autophagy by enhancing the expression of mitophagy-related protein. Dex inhibited the generation of reactive oxygen species (ROS) and the activation of the NLRP3 inflammasome what significantly amelio-rating postoperative cognitive dysfunction.