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

Duan,Jiajia; Yuan,Wen; Jiang,Juan; Wang,Jikai; Yan,Xiaoxin; Liu,Fei; Liu,Aihua

doi:10.3892/mmr.2023.12934

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

Authors:
- Jiajia Duan
- Wen Yuan
- Juan Jiang
- Jikai Wang
- Xiaoxin Yan
- Fei Liu
- Aihua Liu
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Affiliations: Department of Neurosurgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China, Department of Neurosurgery, Zhuzhou Central Hospital, Zhuzhou, Hunan 412000, P.R. China, Department of Anatomy and Neurobiology, Xiangya Medicine School, Central South University, Changsha, Hunan 410000, P.R. China, Department of Neurosurgery, The Fifth Sun Yet‑sen Hospital, Sun Yet‑sen University, Zhuhai, Guangdong 519000, P.R. China
Published online on: January 9, 2023 https://doi.org/10.3892/mmr.2023.12934
Article Number: 47
Copyright: © Duan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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