ASK1 抑制剂 NQDI-1 通过 ASK1/p38 和 JNK 信号通路降低大鼠蛛网膜下腔出血后早期脑损伤的氧化应激和神经细胞凋亡。,Molecular Medicine Reports

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ASK1 抑制剂 NQDI-1 通过 ASK1/p38 和 JNK 信号通路降低大鼠蛛网膜下腔出血后早期脑损伤的氧化应激和神经细胞凋亡。
Molecular Medicine Reports ( IF 3.4 ) Pub Date : 2023-01-12 , DOI: 10.3892/mmr.2023.12934
Jiajia Duan ₁ , Wen Yuan ₂ , Juan Jiang ₃ , Jikai Wang ₄ , Xiaoxin Yan ₃ , Fei Liu ₄ , Aihua Liu ₁

Affiliation

氧化应激和神经细胞凋亡是蛛网膜下腔出血 (SAH) 后的关键病理过程。本研究评估了细胞凋亡信号调节激酶 1 (ASK1) 抑制剂乙基-2,7-二氧代-2,7-二氢-3H-萘酚 (1,2,3-) 的抗氧化和抗凋亡神经保护作用de)喹啉-1-羧酸盐 (NQDI-1) 在大鼠模型中 SAH 后早期脑损伤 (EBI) 中的作用。共使用191只大鼠，采用单丝穿孔法诱导SAH模型。随后使用蛋白质印迹法检测蛋白质的内源性表达水平。然后使用免疫荧光来确认 ASK1 的神经细胞定位。SAH 后 24 小时使用改良的 Garcia 评分和束平衡测试评估短期神经功能，而长期神经功能是使用转棒试验和莫里斯水迷宫试验进行评估的。在 SAH 后 24 小时，通过 TUNEL 染色评估神经元的凋亡，并通过二氢乙锭染色评估氧化应激。SAH 后磷酸化 (p-)ASK1 和 ASK1 的蛋白表达水平上升。NQDI-1 在 SAH 后 1 小时脑室内注射，显示短期和长期神经功能均有显着改善，并显着减少氧化应激和神经元细胞凋亡。注射 NQDI-1 导致 p-ASK1、p-p38、p-JNK、4 羟基壬烯醛和 Bax 的蛋白质表达水平显着降低，并显着增加血红素加氧酶 1 和 Bcl-2 的蛋白质表达水平。使用 p38 抑制剂 BMS-582949 或 JNK 抑制剂 SP600125 分别导致 p-p38 或 p-JNK 的蛋白表达水平显着降低，并显着降低氧化应激和神经细胞凋亡；然而，这些抑制剂并未证明对 p‑ASK1 或 ASK1 蛋白表达水平有影响。总之，用 NQDI-1 治疗可以改善大鼠 SAH 后 EBI 的神经功能并减少氧化应激和神经元凋亡，这可能是通过抑制 ASK1 磷酸化以及 ASK1/p38 和 JNK 信号通路。NQDI-1 可能被认为是治疗 SAH 患者的潜在药物。这些抑制剂未证明对 p‑ASK1 或 ASK1 蛋白表达水平有影响。总之，用 NQDI-1 治疗可以改善大鼠 SAH 后 EBI 的神经功能并减少氧化应激和神经元凋亡，这可能是通过抑制 ASK1 磷酸化以及 ASK1/p38 和 JNK 信号通路。NQDI-1 可能被认为是治疗 SAH 患者的潜在药物。这些抑制剂未证明对 p‑ASK1 或 ASK1 蛋白表达水平有影响。总之，用 NQDI-1 治疗可以改善大鼠 SAH 后 EBI 的神经功能并减少氧化应激和神经元凋亡，这可能是通过抑制 ASK1 磷酸化以及 ASK1/p38 和 JNK 信号通路。NQDI-1 可能被认为是治疗 SAH 患者的潜在药物。

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ASK1 inhibitor NQDI‑1 decreases oxidative stress and neuroapoptosis via the ASK1/p38 and JNK signaling pathway in early brain injury after subarachnoid hemorrhage in rats.

Oxidative stress and neuroapoptosis are key pathological processes after subarachnoid hemorrhage (SAH). The present study evaluated the anti‑oxidation and anti‑apoptotic neuroprotective effects of the apoptosis signal‑regulating kinase 1 (ASK1) inhibitor ethyl‑2,7‑dioxo‑2,7‑dihydro‑3H‑naphtho(1,2,3‑de)quinoline‑1‑carboxylate (NQDI‑1) in early brain injury (EBI) following SAH in a rat model. A total of 191 rats were used and the SAH model was induced using monofilament perforation. Western blotting was subsequently used to detect the endogenous expression levels of proteins. Immunofluorescence was then used to confirm the nerve cellular localization of ASK1. Short‑term neurological function was assessed using the modified Garcia scores and the beam balance test 24 h after SAH, whereas long‑term neurological function was assessed using the rotarod test and the Morris water maze test. Apoptosis of neurons was assessed by TUNEL staining and oxidative stress was assessed by dihydroethidium staining 24 h after SAH. The protein expression levels of phosphorylated (p‑)ASK1 and ASK1 rose following SAH. NQDI‑1 was intracerebroventricularly injected 1 h after SAH and demonstrated significant improvements in both short and long‑term neurological function and significantly reduced oxidative stress and neuronal apoptosis. Injection of NQDI‑1 caused a significant decrease in protein expression levels of p‑ASK1, p‑p38, p‑JNK, 4 hydroxynonenal, and Bax and significantly increased the protein expression levels of heme oxygenase 1 and Bcl‑2. The use of the p38 inhibitor BMS‑582949 or the JNK inhibitor SP600125 led to significant decreases in the protein expression levels of p‑p38 or p‑JNK, respectively, and a significant reduction in oxidative stress and neuronal apoptosis; however, these inhibitors did not demonstrate an effect on p‑ASK1 or ASK1 protein expression levels. In conclusion, treatment with NQDI‑1 improved neurological function and decreased oxidative stress and neuronal apoptosis in EBI following SAH in rats, possibly via inhibition of ASK1 phosphorylation and the ASK1/p38 and JNK signaling pathway. NQDI‑1 may be considered a potential agent for the treatment of patients with SAH.

更新日期：2023-01-12

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