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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-...

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Autores principales: Duan, Jiajia, Yuan, Wen, Jiang, Juan, Wang, Jikai, Yan, Xiaoxin, Liu, Fei, Liu, Aihua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879074/
https://www.ncbi.nlm.nih.gov/pubmed/36633130
http://dx.doi.org/10.3892/mmr.2023.12934
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author Duan, Jiajia
Yuan, Wen
Jiang, Juan
Wang, Jikai
Yan, Xiaoxin
Liu, Fei
Liu, Aihua
author_facet Duan, Jiajia
Yuan, Wen
Jiang, Juan
Wang, Jikai
Yan, Xiaoxin
Liu, Fei
Liu, Aihua
author_sort Duan, Jiajia
collection PubMed
description 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)quinoline1-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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spelling pubmed-98790742023-02-08 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 Mol Med Rep Articles 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)quinoline1-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. D.A. Spandidos 2023-01-09 /pmc/articles/PMC9879074/ /pubmed/36633130 http://dx.doi.org/10.3892/mmr.2023.12934 Text en Copyright: © Duan et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Duan, Jiajia
Yuan, Wen
Jiang, Juan
Wang, Jikai
Yan, Xiaoxin
Liu, Fei
Liu, Aihua
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879074/
https://www.ncbi.nlm.nih.gov/pubmed/36633130
http://dx.doi.org/10.3892/mmr.2023.12934
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