Glutathione alleviates acute intracerebral hemorrhage injury via reversing mitochondrial dysfunction

Xiaojun Diao; Zixian Zhou; Wenjing Xiang; Yanlin Jiang; Ning Tian; Xiaoling Tang; Sangsang Chen; Jian Wen; Meiling Chen; Kaixiang Liu; Qinghua Li; Rujia Liao

doi:10.1016/j.brainres.2019.146514

Glutathione alleviates acute intracerebral hemorrhage injury via reversing mitochondrial dysfunction

Brain Res. 2020 Jan 15:1727:146514. doi: 10.1016/j.brainres.2019.146514. Epub 2019 Oct 16.

Authors

Xiaojun Diao¹, Zixian Zhou², Wenjing Xiang², Yanlin Jiang³, Ning Tian⁴, Xiaoling Tang⁵, Sangsang Chen⁵, Jian Wen⁶, Meiling Chen⁵, Kaixiang Liu⁵, Qinghua Li⁷, Rujia Liao⁸

Affiliations

¹ Department of Neurology, Xiangya Hospital, Central South University, Changsha 410000, China; Guilin Medical University, Guilin 541004, China.
² Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China.
³ Department of Pharmacology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China.
⁴ Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541004, China.
⁵ Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China.
⁶ Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541004, China.
⁷ Department of Neurology, Xiangya Hospital, Central South University, Changsha 410000, China; Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541004, China. Electronic address: qhli1999@163.com.cn.
⁸ Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin 541004, China; Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin 541004, China. Electronic address: liaorujia@hotmail.com.

PMID: 31628933
DOI: 10.1016/j.brainres.2019.146514

Abstract

Glutathione (GSH) has been studied for its neuroprotection value in several diseases, but the effect of GSH on intracerebral hemorrhage (ICH) is unclear. In this study, we examined the protective effects of GSH in an experimentally induced ICH model and investigated the relative mechanisms. Adult male C57BL/6j mice were randomized into Sham, ICH and GSH treatment groups. GSH was injected with the dose of 50, 100 or 200 mg/kg once per day for 3 days, starting immediately after operation. The results revealed a GSH-mediated improvement of neurological deficits score (NDS), motor and sensory functions impairment in a dose-dependent manner three days post ICH (p < 0.01, GSH 200 vs ICH. Sham, n = 12; ICH, n = 9; GSH 50, n = 10; GSH 100, n = 10; GSH 200, n = 11) in addition to significantly reduced mortality rate (p = 0.2632, GSH 200 vs ICH. n = 12 per group) and damage volume (p < 0.05, GSH 200 vs ICH. n = 12 per group). GSH treatment also attenuated injury measured by decreased brain edema (p < 0.05, GSH 200 vs ICH. Sham, n = 10; ICH, n = 10; GSH 200, n = 12), blood-brain barrier disruption (p < 0.05, GSH 200 vs ICH. Sham, n = 10; ICH, n = 10; GSH 200, n = 12), and histopathological damage (p < 0.05, GSH 200 vs ICH. Sham, n = 6; ICH, n = 6; GSH 200, n = 8) 72 h after ICH. In addition, GSH treatment also decreased cell apoptosis (p < 0.01, GSH 200 vs ICH. Sham, n = 6; ICH, n = 6; GSH 200, n = 8) and resulted in up-regulated protein expression of complex I (p < 0.01, GSH 200 vs ICH. Sham, n = 6; ICH, n = 6; GSH 200, n = 8), which was consistent with an overall up-regulation of complex I function in mitochondria using Oxygraph-2 K high resolution respirometry (p < 0.05, GSH 200 vs ICH. Sham, n = 4; ICH, n = 5; GSH 200, n = 6). In conclusion, GSH effectively improved the prognosis of ICH mice by attenuating neurological impairment, decreasing neural damage, and inhibiting apoptosis. The neuroprotection by GSH resulted from the up-regulation of mitochondrial oxidative respiration function. The results of our study suggest that GSH can be a potential therapeutic agent for ICH.

Keywords: Acute stage; Glutathione; Intracerebral hemorrhage; Mitochondrial; Mitochondrial oxidative respiration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Disease
Animals
Apoptosis / drug effects
Brain Edema / drug therapy
Brain Edema / etiology
Cerebral Hemorrhage / complications
Cerebral Hemorrhage / drug therapy*
Glutathione / administration & dosage
Glutathione / pharmacology*
Male
Mice
Mice, Inbred C57BL
Mitochondria / drug effects*
Mitochondria / metabolism
Neuroprotection*
Neuroprotective Agents / administration & dosage
Neuroprotective Agents / pharmacology*

Substances

Neuroprotective Agents
Glutathione