芳香烃受体
氧化应激
犬尿氨酸途径
线粒体
犬尿氨酸
细胞生物学
活性氧
喹啉酸
细胞凋亡
药理学
化学
兴奋毒性
生物
程序性细胞死亡
生物化学
转录因子
色氨酸
氨基酸
基因
作者
Reng Ren,Yuanjian Fang,Prativa Sherchan,Qin Lü,Cameron Lenahan,Junyi Zhang,Jianmin Zhang,Jiping Tang
标识
DOI:10.1089/ars.2021.0215
摘要
Aims: Oxidative stress and neuronal apoptosis play crucial roles in the pathological processes of secondary injury after intracerebral hemorrhage (ICH). Aryl hydrocarbon receptor (AHR), together with its endogenous ligand kynurenine, is known to mediate free radical accumulation and neuronal excitotoxicity in central nervous systems. Herein, we investigate the pathological roles of kynurenine/AHR after ICH. Results: Endogenous AHR knockout alleviated reactive oxygen species accumulation and neuronal apoptosis in ipsilateral hemisphere at 48 h after ICH in mice. The ICH insult resulted in an increase of total and nucleus AHR protein levels and AHR transcriptional activity. Inhibition of AHR provided both short- and long- term neurological benefits by attenuating mitochondria-mediated oxidative stress and neuronal apoptosis after ICH in mice. RhoA-Bax signaling activated mitochondrial death pathway and participated in deleterious actions of AHR. Finally, we reported that exogenous kynurenine aggravated AHR activation and mediated the brain mentioned earlier. Male animals were used in the experiments. Innovation: We show for the first time that kynurenine/AHR mediates mitochondria death and free radical accumulation, at least partially via the RhoA/Bax signaling pathway. Pharmacological antagonists of AHR and kynurenine may ameliorate neurobehavioral function and improve the prognosis of patients with ICH. Conclusion: Kynurenine/AHR may serve as a potential therapeutic target to attenuate mitochondria-mediated oxidative stress and neuronal cells impairment in patients with ICH. Antioxid. Redox Signal. 37, 1111–1129.
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