Excessive intragastric alcohol administration exacerbates hepatic encephalopathy and provokes neuronal cell death in male rats with chronic liver disease

IF 2.9 3区 医学 Q2 NEUROSCIENCES
Farzaneh Tamnanloo, Xiaoru Chen, Mariana M. Oliveira, Mélanie Tremblay, Christopher F. Rose
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Abstract

Hepatic encephalopathy (HE) is defined as decline in neurological function during chronic liver disease (CLD). Alcohol is a major etiological factor in the pathogenesis of fibrosis/cirrhosis and has also been documented to directly impact the brain. However, the role of alcohol in the development of HE in CLD remains unclear. Here, we investigated the impact of excessive alcohol administration on neurological deterioration in rats with CLD. Starting day 7 post-BDL surgery, rats were administered alcohol twice daily (51% v/v ethanol, 3 g/kg, via gavage) for 4 weeks. Motor coordination was assessed weekly using rotarod and anxiety-like behavior was evaluated with open field and elevated plus maze at 5 weeks. Upon sacrifice, brains were collected for western blot and immunohistochemical analyses to investigate neuronal integrity and oxidative stress status. Alcohol worsened motor coordination performance and increased anxiety-like behavior in BDL rats. Impairments were associated with decreased neuronal markers of NeuN and SMI311, increased apoptotic markers of cleaved/pro-caspase-3 and Bax/Bcl2, increased necroptosis markers of pRIP3 and pMLKL, decreased total antioxidant capacity (TAC), and increased 4-hydroxynonenal (4-HNE)modified proteins in the cerebellum of BDL-alcohol rats when compared to respective controls. Immunofluorescence confirmed the colocalization of cleaved caspase-3 and pMLKL in the granular neurons of the cerebellum of BDL-alcohol rats. Excessive alcohol consumption exacerbates HE which leads to associated apoptotic and necroptotic neuronal loss in the cerebellum of BDL-alcohol rats. Additionally, higher levels of 4-HNE and decreased TAC in the cerebellum of BDL-alcohol rats suggest oxidative stress is the triggering factor of apoptotic and necroptotic neuronal loss/injury.

Abstract Image

雄性慢性肝病大鼠胃内摄入过量酒精会加重肝性脑病并导致神经细胞死亡
肝性脑病(HE)是指慢性肝病(CLD)期间神经功能的衰退。酒精是肝纤维化/肝硬化发病机制中的一个主要致病因素,也被证实会直接影响大脑。然而,酒精在肝纤维化/肝硬化中的作用仍不清楚。在此,我们研究了过量饮酒对 CLD 大鼠神经系统恶化的影响。从 BDL 术后第 7 天开始,每天给大鼠注射两次酒精(51% v/v 乙醇,3 克/千克,灌胃),持续 4 周。每周用旋转木马评估大鼠的运动协调性,5周时用开放场地和高架加迷宫评估大鼠的焦虑行为。牺牲后,收集大脑进行 Western 印迹和免疫组化分析,以研究神经元的完整性和氧化应激状态。酒精恶化了BDL大鼠的运动协调能力,并增加了焦虑样行为。与各对照组相比,BDL-酒精大鼠小脑中的神经元标记物NeuN和SMI311减少、凋亡标记物裂解/pro-caspase-3和Bax/Bcl2增加、坏死标记物pRIP3和pMLKL增加、总抗氧化能力(TAC)降低以及4-羟基壬烯醛(4-HNE)修饰蛋白增加。免疫荧光证实,在BDL-酒精大鼠小脑的颗粒神经元中,有裂解的caspase-3和pMLKL共定位。过量饮酒会加重 HE,导致 BDL-酒精大鼠小脑中相关神经元凋亡和坏死。此外,BDL-酒精大鼠小脑中较高水平的4-HNE和较低的TAC表明,氧化应激是导致神经元凋亡和坏死/损伤的诱发因素。
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来源期刊
Journal of Neuroscience Research
Journal of Neuroscience Research 医学-神经科学
CiteScore
9.50
自引率
2.40%
发文量
145
审稿时长
1 months
期刊介绍: The Journal of Neuroscience Research (JNR) publishes novel research results that will advance our understanding of the development, function and pathophysiology of the nervous system, using molecular, cellular, systems, and translational approaches. JNR covers both basic research and clinical aspects of neurology, neuropathology, psychiatry or psychology. The journal focuses on uncovering the intricacies of brain structure and function. Research published in JNR covers all species from invertebrates to humans, and the reports inform the readers about the function and organization of the nervous system, with emphasis on how disease modifies the function and organization.
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