Thangwong Phakkawat, Jearjaroen Pranglada, Govitrapong Piyarat, Tocharus Chainarong, Tocharus Jiraporn
Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Graduate School, Chiang Mai University, Chiang Mai 50200, Thailand.
Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Biochem Pharmacol. 2022 Apr;198:114980. doi: 10.1016/j.bcp.2022.114980. Epub 2022 Feb 24.
Chronic cerebral hypoperfusion (CCH) is the most common cause of cognitive impairment, which is commonly found in Alzheimer's disease (AD) and vascular dementia (VaD). Recently, studies have demonstrated that melatonin is an effective treatment in various neurodegenerative diseases. In this study, we aimed to investigate the effects of melatonin on CCH-induced AD pathology, endoplasmic reticulum (ER) stress, and synaptic plasticity, all of which are correlated with the activation of oxidative stress, apoptosis, and cognitive impairment. CCH was induced in male Wistar rats by bilateral common carotid artery occlusion (2VO). After surgery, rats were treated with melatonin (10 mg/kg) or piracetam (600 mg/kg) by oral gavage once a day for 4 weeks. At the end of the experiment, all rats were assessed for memory impairment by using the Morris water maze test. Subsequently, rats were sacrificed, and brains were removed to determine the levels of beta-amyloid (Aβ), malondialdehyde (MDA); the acetylcholinesterase (AChE) activity; subjected to terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL); and subjected to western blotting of proteins related to memory, AD pathology, oxidative stress, ER stress, and apoptosis. Melatonin alleviated brain injury during 2VO induction, as revealed by decreased the expression of AD markers, attenuated oxidative stress, suppressed the expression of proteins related to ER stress, apoptosis, and stimulated the expression of the synaptic markers resulting in promoted cognitive function. Therefore, our data demonstrated that melatonin ameliorated cognitive impairment in the 2VO model, and these beneficial effects were associated with reduction in oxidative stress, ER stress, and apoptosis.
慢性脑灌注不足（CCH）是认知障碍最常见的原因，常见于阿尔茨海默病（AD）和血管性痴呆（VaD）。最近，研究表明褪黑素是治疗各种神经退行性疾病的有效药物。在本研究中，我们旨在研究褪黑素对CCH诱导的AD病理、内质网（ER）应激和突触可塑性的影响，所有这些都与氧化应激、细胞凋亡和认知障碍的激活相关。通过双侧颈总动脉闭塞（2VO）在雄性Wistar大鼠中诱导CCH。手术后，大鼠每天经口灌胃给予褪黑素（10mg/kg）或吡拉西坦（600mg/kg），持续4周。在实验结束时，使用Morris水迷宫试验评估所有大鼠的记忆障碍。随后，处死大鼠，取出大脑以测定β-淀粉样蛋白（Aβ）、丙二醛（MDA）的水平；乙酰胆碱酯酶（AChE）活性；进行末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）；并对与记忆、AD病理、氧化应激、ER应激和细胞凋亡相关的蛋白质进行蛋白质印迹分析。褪黑素减轻了2VO诱导过程中的脑损伤，表现为AD标志物表达降低、氧化应激减轻、ER应激和细胞凋亡相关蛋白表达受到抑制，并刺激了突触标志物的表达，从而促进了认知功能。因此，我们的数据表明褪黑素改善了2VO模型中的认知障碍，这些有益作用与氧化应激、ER应激和细胞凋亡的减少有关。
