Postgraduate Training Base of The General Hospital of Northern Theater Command, Jinzhou Medical University, Jinzhou, Liaoning 121013, P.R. China.
Department of Anesthesiology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China.
Mol Med Rep. 2021 Apr;23(4). doi: 10.3892/mmr.2021.11933. Epub 2021 Mar 2.
Postoperative cognitive dysfunction (POCD) is a common complication following cardiopulmonary bypass (CPB). U50488H, a κ‑opioid 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 CPB‑induced POCD and brain damage and explored the regulatory mechanism of the PI3K/AKT/nuclear factor erythroid 2‑related factor 2 (Nrf2)/heme oxygenase (HO)‑1 pathway. Sprague‑Dawley rats were divided into the following groups: Sham operation (Sham group), CPB (CPB group), KOR agonist (U50488H) + CPB (U50488H group), CPB + U50488H + HO‑1 antagonist (ZnPP‑IX; 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. Enzyme‑linked immunosorbent assays were used to detect inflammatory and oxidative stress factors. Western blotting was used to examine the expression of PI3K/AKT/Nrf2/HO‑1‑related 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 HO‑1 and thioredoxin 1 (Trx1) expression. In CPB rats treated with PI3K inhibitors, less Nrf2 was detected in the nucleus and HO‑1 and Trx‑1 expression levels were reduced in the nucleus. Therefore, U50488H, a KOR agonist, can activate Nrf2/HO‑1 via the PI3K/AKT pathway to improve cognitive function and reduce brain damage in CPB rats.
术后认知功能障碍（POCD）是体外循环（CPB）后常见的并发症。U50488H 是一种 κ-阿片受体（KOR）激动剂，可特异性激活海马神经细胞上的 KOR，产生神经保护作用。本研究建立 CPB 大鼠模型，观察 U50488H 对 CPB 诱导的 POCD 和脑损伤的保护作用，并探讨 PI3K/AKT/核因子红细胞 2 相关因子 2（Nrf2）/血红素加氧酶（HO）-1 通路的调节机制。将 Sprague-Dawley 大鼠分为以下几组：假手术（Sham 组）、CPB（CPB 组）、KOR 激动剂（U50488H）+CPB（U50488H 组）、CPB+U50488H+HO-1 拮抗剂（ZnPP-IX；ZnPP 组）和 CPB+U50488H+PI3K 拮抗剂（LY294002；LY294002 组），每组 10 只大鼠。采用神经功能评分和 Morris 水迷宫试验评估认知功能；采用苏木精和伊红及末端脱氧核苷酸转移酶 dUTP 缺口末端标记法观察大鼠海马神经元损伤；免疫荧光法检测海马中活性氧、胶质纤维酸性蛋白和 Nrf2 的表达；酶联免疫吸附试验检测炎症和氧化应激因子；Western blot 检测 PI3K/AKT/Nrf2/HO-1 相关蛋白的表达。结果表明，U50488H 可显著降低 CPB 诱导的 POCD 大鼠的神经功能评分，缓解认知功能障碍，减少海马神经元损伤，抑制细胞凋亡率，修复 CPB 引起的氧化应激损伤，减轻脑损伤。此外，U50488H 可促进 Nrf2 入核，上调 HO-1 和硫氧还蛋白 1（Trx1）的表达。在 CPB 大鼠中给予 PI3K 抑制剂后，核内 Nrf2 减少，核内 HO-1 和 Trx-1 的表达水平降低。因此，KOR 激动剂 U50488H 可通过 PI3K/AKT 通路激活 Nrf2/HO-1，改善 CPB 大鼠的认知功能，减轻脑损伤。
