Abstract
Objective Cardiopulmonary bypass (CPB) is an important cardiac operation and also a high-risk procedure, leading to postoperative neurocognitive disorder. However, there are few effective drugs to treat the aftermath of CPB. Therefore, we observe the effect of kappa opioid receptor (KOR) agonist on cognitive disorders of rats after cardiopulmonary bypass (CPB) and investigate the mechanism of the Ca2+/calmodulin-dependent protein kinase (CaMKII)/cAMP responsive element-binding protein (CREB) pathway. Methods A total of 40 Sprague Dawley rats were randomly divided into the sham operation group (sham group, n = 10), CPB model group (CPB group, n = 10), CPB + KOR agonist U50488H group (UH group, n = 10), and CPB + specific CaMKII antagonist + U50488H group (CKU group, n = 10). The changes in the rats' cognitive function were evaluated using the Morris water maze, the hippocampal histopathological changes were observed via hematoxylin-eosin (H&E) staining, and the apoptosis rate of neuronal cells was detected through terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. Moreover, enzyme-linked immunosorbent assay (ELISA) was applied to examine the changes in brain injury markers, inflammatory factors, and oxidative stress factors. The hippocampal variations in Ca2+ concentration and oxidative stress index (ROS) levels were measured by immunofluorescence staining, and western blotting was performed to determine the expression changes in the Ca2+/CaMKII/CREB pathway. Results The KOR agonist could shorten latency, increase the swimming distance and residence time in the target quadrant, and ameliorate postoperative neurocognitive disorder (PND). Meanwhile, the KOR agonist relieved CPB-induced hippocampal and oxidative stress injuries, reduced NSE and S-100β expression, decreased the apoptosis rate, and repressed the inflammatory response, which alleviated the brain injury. In addition, U50488H was able to decrease Ca2+ influx and glutamate (Glu) level, inhibit N-methyl-D-aspartate receptor (NMDAR) expression, upregulate CaMKII expression, promote CREB phosphorylation, and increase the brain-derived neurotrophic factor (BDNF) level in CPB rats. However, the protective effects of KORs against PND were suppressed following the application of the CaMKII-specific antagonist. Conclusion The KOR agonist activates the Ca2+/CaMKII/CREB pathway, which improves the brain injury and relieves PND in CPB rats.
Highlights
Cardiopulmonary bypass (CPB) is mainly applied in cardiac operations for ischemic, valvular, and congenital heart diseases, and aortic dissection [1]
kappa opioid receptor (KOR) Agonist Ameliorated Brain Injury and Alleviated postoperative neurocognitive disorder (PND) in CPB Rats. e water maze test was applied to determine the cognitive function of the rats
The KOR agonist U50488H could shorten the latency, increase the swimming distance and extend the residence time in the target quadrant (Figure 1(a)). e histopathological changes in the hippocampus were observed by H&E staining, and the results indicated that the CPB group had severe hippocampus injury, disorderly arranged cells, and a gradual widening of the intercellular space
Summary
Cardiopulmonary bypass (CPB) is mainly applied in cardiac operations for ischemic, valvular, and congenital heart diseases, and aortic dissection [1]. Postoperative neurocognitive disorder (PND) has become one of the leading causes of disability and death of patients after cardiac operation under CPB [2]. Neuroinflammation, especially inflammation in the hippocampal tissues, is a major reason of PND onset [5] Both aged rats and mice manifest significant memory and learning deficits that are accompanied with the activation of microglial cells and increase in tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1β expressions in the hippocampus, resulting in nerve cell apoptosis and reduced learning and memory abilities [6, 7]. Decreasing the release of neuroinflammatory factors, in the hippocampus and restraining Ca2+ influx, has crucial clinical significance in improving brain injury and in preventing and treating PND, caused by cardiac operation under CPB
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