Shawki Samar M, Saad Mohammed A, Rahmo Rania M, Wadie Walaa, El-Abhar Hanan S
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Front Pharmacol. 2021 Dec 22;12:731483. doi: 10.3389/fphar.2021.731483. eCollection 2021.
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, psychiatric, and cognitive abnormalities. The antidiabetic drug liraglutide possesses a neuroprotective potential against several neurodegenerative disorders; however, its role in Huntington's disease (HD) and the possible mechanisms/trajectories remain elusive, which is the aim of this work. Liraglutide (200 μg/kg, s.c) was administered to rats intoxicated with 3-nitropropionic acid (3-NP) for 4 weeks post HD model induction. Liraglutide abated the 3-NP-induced neurobehavioral deficits (open field and elevated plus maze tests) and histopathological changes. Liraglutide downregulated the striatal mRNA expression of HSP 27, PBR, and GFAP, while it upregulated that of DARPP32. On the molecular level, liraglutide enhanced striatal miR-130a gene expression and TrKB protein expression and its ligand BDNF, while it reduced the striatal protein content and mRNA expression of the death receptors sortilin and p75NTR, respectively. It enhanced the neuroprotective molecules cAMP, p-PI3K, p-Akt, and p-CREB, besides modulating the -GSK-3β/-β-catenin axis. Liraglutide enhanced the antioxidant transcription factor Nrf2, abrogated TBARS, upregulated both Bcl2 and Bcl-XL, and downregulated Bax along with decreasing caspase-3 activity. Therefore, liraglutide exerts a neurotherapeutic effect on 3-NP-treated rats that is, besides the upturn of behavioral and structural findings, it at least partially, increased miR-130a and modulated PI3K/Akt/CREB/BDNF/TrKB, sortilin, and p75NTR, and Akt/GSK-3β/-β-catenin trajectories besides its capacity to decrease apoptosis and oxidative stress, as well as its neurotrophic activity.
亨廷顿舞蹈症（HD）是一种常染色体显性遗传的神经退行性疾病，其特征为进行性运动、精神和认知异常。抗糖尿病药物利拉鲁肽对多种神经退行性疾病具有神经保护潜力；然而，其在亨廷顿舞蹈症（HD）中的作用以及可能的机制/途径仍不清楚，这正是本研究的目的。在HD模型诱导后4周，给用3-硝基丙酸（3-NP）中毒的大鼠皮下注射利拉鲁肽（200μg/kg）。利拉鲁肽减轻了3-NP诱导的神经行为缺陷（旷场试验和高架十字迷宫试验）以及组织病理学变化。利拉鲁肽下调了纹状体中HSP 27、外周型苯二氮䓬受体（PBR）和胶质纤维酸性蛋白（GFAP）的mRNA表达，同时上调了多巴胺和环磷腺苷调节的磷酸蛋白32（DARPP32）的表达。在分子水平上，利拉鲁肽增强了纹状体中miR-130a基因表达以及酪氨酸激酶B（TrKB）蛋白表达及其配体脑源性神经营养因子（BDNF），同时分别降低了纹状体中死亡受体sortilin和p75神经营养因子受体（p75NTR）的蛋白含量和mRNA表达。除了调节糖原合成酶激酶-3β（GSK-3β）/β-连环蛋白轴外，它还增强了神经保护分子环磷酸腺苷（cAMP）、磷酸化磷脂酰肌醇-3激酶（p-PI3K）、磷酸化蛋白激酶B（p-Akt）和磷酸化环磷腺苷反应元件结合蛋白（p-CREB）。利拉鲁肽增强了抗氧化转录因子核因子E2相关因子2（Nrf2），消除了丙二醛（TBARS），上调了B细胞淋巴瘤/白血病-2（Bcl2）和Bcl-2相关X蛋白（Bcl-XL），下调了Bax并降低了半胱天冬酶-3（caspase-3）活性。因此，利拉鲁肽对3-NP处理的大鼠具有神经治疗作用，除了改善行为和结构方面的结果外，它至少部分地增加了miR-130a并调节了磷脂酰肌醇-3激酶/蛋白激酶B/环磷腺苷反应元件结合蛋白/脑源性神经营养因子/酪氨酸激酶B、sortilin和p75NTR以及蛋白激酶B/糖原合成酶激酶-3β/β-连环蛋白途径，此外还具有降低细胞凋亡和氧化应激的能力以及神经营养活性。
