RESUMO
Postoperative cognitive dysfunction (POCD) is a common complication following cardiopulmonary bypass (CPB). U50488H, a κopioid receptor (KOR) agonist, can specifically activate KORs on hippocampal nerve cells, resulting in neuroprotective effects. The present study established a CPB rat model, observed the protective effect of U50488H on CPBinduced POCD and brain damage and explored the regulatory mechanism of the PI3K/AKT/nuclear factor erythroid 2related factor 2 (Nrf2)/heme oxygenase (HO)1 pathway. SpragueDawley rats were divided into the following groups: Sham operation (Sham group), CPB (CPB group), KOR agonist (U50488H) + CPB (U50488H group), CPB + U50488H + HO1 antagonist (ZnPPIX; ZnPP group) and CPB + U50488H + PI3K antagonist (LY294002; LY294002 group), with 10 rats in each group. Neurological scores and the Morris water maze test were used to evaluate cognitive function; hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed to observe hippocampal neuron damage in rats. Immunofluorescence was used to detect reactive oxygen species, glial fibrillary acidic protein and Nrf2 expression in the hippocampus. Enzymelinked immunosorbent assays were used to detect inflammatory and oxidative stress factors. Western blotting was used to examine the expression of PI3K/AKT/Nrf2/HO1related proteins. It was demonstrated that U50488H significantly reduced the neural function score of rats with POCD induced by CPB, relieved cognitive dysfunction, reduced hippocampal neuron damage, inhibited the rate of apoptosis, repaired oxidative stress injury and protected against brain damage caused by CPB. In addition, U50488H could promote Nrf2 entry into the nucleus and upregulate HO1 and thioredoxin 1 (Trx1) expression. In CPB rats treated with PI3K inhibitors, less Nrf2 was detected in the nucleus and HO1 and Trx1 expression levels were reduced in the nucleus. Therefore, U50488H, a KOR agonist, can activate Nrf2/HO1 via the PI3K/AKT pathway to improve cognitive function and reduce brain damage in CPB rats.