Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Fundam Clin Pharmacol. 2021 Feb;35(1):113-130. doi: 10.1111/fcp.12584. Epub 2021 Jan 2.
Abuse of alcohol triggers neurodegeneration in human brain. Minocycline has characteristics conferring neuroprotection. Current study evaluates the role of the CREB-BDNF signaling pathway in mediating minocycline's neuroprotective effects against alcohol-induced neurodegeneration. Seventy adult male rats were randomly split into groups 1 and 2 that received saline and alcohol (2 g/kg/day by gavage, once daily), respectively, and groups 3, 4, 5, and 6 were treated simultaneously with alcohol and minocycline (10, 20, 30 and 40 mg/kg I.P, respectively) for 21 days. Group 7 received minocycline alone (40 mg/kg, i.p) for 21 days. Morris water maze (MWM) has been used to assess cognitive activity. Hippocampal neurodegenerative and histological parameters as well as cyclic AMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) levels were assessed. Alcohol impaired cognition, and concurrent therapy with various minocycline doses attenuated alcohol-induced cognition disturbances. Additionally, alcohol administration boosted lipid peroxidation and levels of glutathione in oxidized form (GSSG), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and Bax protein, while decreased reducing type of glutathione (GSH), Bcl-2 protein, phosphorylated CREB, and BDNF levels in rat hippocampus. Alcohol also decreased the activity in the hippocampus of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). In comparison, minocycline attenuated alcohol-induced neurodegeneration; elevating expression levels of P-CREB and BDNF and inhibited alcohol induced histopathological changes in both dentate gyrus (DG) and CA1 of hippocampus. Thus, minocycline is likely to provide neuroprotection against alcohol-induced neurodegeneration through mediation of the P-CREB/BDNF signaling pathway.
酒精滥用会引发人脑神经退行性病变。米诺环素具有神经保护特性。本研究评估了 CREB-BDNF 信号通路在介导米诺环素对酒精诱导的神经退行性变的神经保护作用中的作用。70 只成年雄性大鼠随机分为 1 组和 2 组，分别给予生理盐水和酒精（灌胃 2 g/kg/天，每天一次），3、4、5 和 6 组同时给予酒精和米诺环素（分别为 10、20、30 和 40 mg/kg 腹腔注射），连续 21 天。第 7 组单独给予米诺环素（40 mg/kg，腹腔注射）21 天。Morris 水迷宫（MWM）用于评估认知活动。评估海马神经退行性变和组织学参数以及环磷腺苷反应元件结合蛋白（CREB）和脑源性神经营养因子（BDNF）水平。酒精损害认知，同时给予不同剂量的米诺环素可减轻酒精引起的认知障碍。此外，酒精给药增加了脂质过氧化和氧化型谷胱甘肽（GSSG）、肿瘤坏死因子-α（TNF-α）、白细胞介素 1β（IL-1β）和 Bax 蛋白的水平，同时降低了还原型谷胱甘肽（GSH）、Bcl-2 蛋白、磷酸化 CREB 和 BDNF 水平在大鼠海马中。酒精还降低了超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GPx）和谷胱甘肽还原酶（GR）在海马中的活性。相比之下，米诺环素减轻了酒精引起的神经退行性变；提高 P-CREB 和 BDNF 的表达水平，并抑制酒精诱导的海马齿状回（DG）和 CA1 区的组织病理学变化。因此，米诺环素可能通过介导 P-CREB/BDNF 信号通路提供对酒精诱导的神经退行性变的神经保护作用。
