Patel Parmi, Faldu Khushboo, Borisa Ankit, Bhatt Hardik, Shah Jigna
Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India.
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India.
Curr Neurovasc Res. 2022;19(3):344-357. doi: 10.2174/1567202619666220908125125.
Alzheimer's Disease (AD) impairs memory and cognitive functions in the geriatric population and is characterized by intracellular deposition of neurofibrillary tangles, extracellular deposition of amyloid plaques, and neuronal degeneration. Literature suggests that latent viral infections in the brain act as prions and promote neurodegeneration. Memantine possesses both anti-viral and N-methyl-D-aspartate (NMDA) receptor antagonistic activity.
This research was designed to evaluate the efficacy of antiviral agents, especially valacyclovir, a prodrug of acyclovir in ameliorating the pathology of AD based on the presumption that anti-viral agents targeting the Herpes Simplex Virus (HSV) can have a protective effect on neurodegenerative diseases like Alzheimer's disease.
Thus, we evaluated acyclovir's potential activity by in-silico computational docking studies against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase 1 (BACE-1). These findings were further evaluated by in-vivo scopolamine-induced cognitive impairment in rats. Two doses of valacyclovir, a prodrug of acyclovir (100 mg/kg and 150 mg/kg orally) were tested.
Genetic Optimisation for Ligand Docking scores and fitness scores of acyclovir were comparable to donepezil. Valacyclovir improved neurobehavioral markers. It inhibited AChE and BuChE (p<0.001) enzymes. It also possessed disease-modifying efficacy as it decreased the levels of BACE-1 (p<0.001), amyloid beta 1-42 (p<0.001), amyloid beta 1-40 (p<0.001), phosphorylatedtau (p<0.001), neprilysin (p<0.01), and insulin-degrading enzyme. It ameliorated neuroinflammation through decreased levels of tumour necrosis factor α (p<0.001), nuclear factor-kappa B (p<0.001), interleukin 6 (p<0.001), interleukin 1 beta (p<0.001), and interferon-gamma (p<0.001). It also maintained synaptic plasticity and consolidated memory. Histopathology showed that valacyclovir could restore cellular density and also preserve the dentate gyrus.
Valacyclovir showed comparable activity to donepezil and thus can be further researched for the treatment of Alzheimer's disease.
阿尔茨海默病（AD）损害老年人群的记忆和认知功能，其特征为神经原纤维缠结的细胞内沉积、淀粉样斑块的细胞外沉积以及神经元变性。文献表明，大脑中的潜伏病毒感染可充当朊病毒并促进神经变性。美金刚具有抗病毒和N-甲基-D-天冬氨酸（NMDA）受体拮抗活性。
本研究旨在评估抗病毒药物，尤其是阿昔洛韦的前体药物伐昔洛韦，基于这样一种假设，即针对单纯疱疹病毒（HSV）的抗病毒药物可能对阿尔茨海默病等神经退行性疾病具有保护作用，从而改善AD的病理状况。
因此，我们通过针对乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BuChE）和β-分泌酶1（BACE-1）的计算机模拟对接研究评估了阿昔洛韦的潜在活性。这些发现通过东莨菪碱诱导的大鼠体内认知障碍进一步评估。测试了两种剂量的伐昔洛韦，即阿昔洛韦的前体药物（口服100mg/kg和150mg/kg）。
阿昔洛韦的配体对接分数和适应度分数的基因优化与多奈哌齐相当。伐昔洛韦改善了神经行为标志物。它抑制了AChE和BuChE（p<0.001）酶。它还具有疾病修饰功效，因为它降低了BACE-1（p<0.001）、淀粉样β蛋白1-42（p<0.001）、淀粉样β蛋白1-40（p<0.001）、磷酸化tau（p<0.001）、中性内肽酶（p<0.01）和胰岛素降解酶的水平。它通过降低肿瘤坏死因子α（p<0.001）、核因子-κB（p<0.001）、白细胞介素6（p<0.001）、白细胞介素1β（p<0.001）和干扰素-γ（p<0.001）的水平改善了神经炎症。它还维持了突触可塑性并巩固了记忆。组织病理学显示伐昔洛韦可以恢复细胞密度并保留齿状回。
伐昔洛韦显示出与多奈哌齐相当的活性，因此可进一步研究用于治疗阿尔茨海默病。
