Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Κasr El-Aini Str, 11562, Cairo, Egypt.
Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Egypt.
Neurochem Int. 2021 Sep;148:105082. doi: 10.1016/j.neuint.2021.105082. Epub 2021 May 28.
Since the role of estrogen in postmenauposal-associated dementia is still debatable, this issue urges the search for other medications. Dimethyl fumarate (DMF) is a drug used for the treatment of multiple sclerosis and has shown a neuroprotective effect against other neurodegenerative diseases. Accordingly, the present study aimed to evaluate the effect of DMF on an experimental model of Alzheimer disease (AD) using D-galactose (D-Gal) administered to ovariectomized (OVX) rats, resembling a postmenopausal dementia paradigm. Adult 18-month old female Wistar rats were allocated into sham-operated and OVX/D-Gal groups that were either left untreated or treated with DMF for 56 days starting three weeks after sham-operation or ovariectomy. DMF succeeded to ameliorate cognitive (learning/short- and long-term memory) deficits and to enhance the dampened overall activity (NOR, Barnes-/Y-maze tests). These behavioral upturns were associated with increased intact neurons (Nissl stain) and a reduction in OVX/D-Gal-mediated hippocampal CA1 neurodegeneration and astrocyte activation assessed as GFAP immunoreactivity. Mechanistically, DMF suppressed the hippocampal contents of AD-surrogate markers; viz., apolipoprotein (APO)-E1, BACE1, Aβ42, and hyperphosphorylated Tau. Additionally, DMF has augmented the neuroprotective parameters p-AKT, its downstream target CREB and BDNF. Besides, it activated AMPK, and enhanced SIRT-1, as well as antioxidant defenses (SOD, GSH). On the other hand, DMF inhibited the transcription factor NF-κB, IL-1β, adiponectin/adiponectin receptor type (AdipoR)1, GSK-3β, and MDA. Accordingly, in this postmenopausal AD model, DMF treatment by pursuing the adiponectin/AdipoR1, AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, and APO-E1 quartet hampered the associated tauo-/amyloidopathy and NF-κB-mediated oxidative/inflammatory responses to advance insights into its anti-amnesic effect.
由于雌激素在绝经后相关痴呆中的作用仍存在争议，因此这一问题促使人们寻找其他药物。富马酸二甲酯（DMF）是一种用于治疗多发性硬化症的药物，已显示出对其他神经退行性疾病的神经保护作用。因此，本研究旨在使用 D-半乳糖（D-Gal）处理去卵巢（OVX）大鼠，建立阿尔茨海默病（AD）的实验模型，评估 DMF 的作用，该模型类似于绝经后痴呆模型。将 18 个月大的成年雌性 Wistar 大鼠分为假手术组和 OVX/D-Gal 组，OVX/D-Gal 组大鼠在假手术或卵巢切除 3 周后开始接受 56 天的 DMF 治疗或不治疗。DMF 成功改善了认知（学习/短期和长期记忆）缺陷，并增强了（NOR、Barnes-/Y 迷宫测试）减弱的整体活动。这些行为改善与海马 CA1 神经退行性变和星形胶质细胞活化（GFAP 免疫反应性）的减少有关，而海马 CA1 神经退行性变和星形胶质细胞活化是由 OVX/D-Gal 介导的。从机制上讲，DMF 抑制了 AD 替代标志物的海马含量；即载脂蛋白（APO）-E1、BACE1、Aβ42 和过度磷酸化 Tau。此外，DMF 增加了神经保护参数 p-AKT、其下游靶点 CREB 和 BDNF。此外，它激活 AMPK，增强 SIRT-1，以及抗氧化防御（SOD、GSH）。另一方面，DMF 抑制了转录因子 NF-κB、IL-1β、脂联素/脂联素受体 1（AdipoR）1、GSK-3β 和 MDA。因此，在这种绝经后 AD 模型中，DMF 通过以下方式治疗：追求脂联素/AdipoR1、AMPK/SIRT-1、AKT/CREB/BDNF、AKT/GSK-3β 和 APO-E1 四重奏，阻止了相关的 tauo-/淀粉样变和 NF-κB 介导的氧化/炎症反应，从而深入了解其抗遗忘作用。
