Insights of Valacyclovir in Treatment of Alzheimer's Disease: Computational Docking Studies and Scopolamine Rat Model.

IF 2 4区医学 Q3 CLINICAL NEUROLOGY Current neurovascular research Pub Date : 2022-01-01 DOI:10.2174/1567202619666220908125125

Parmi Patel, Khushboo Faldu, Ankit Borisa, Hardik Bhatt, Jigna Shah

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Abstract

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: Valacyclovir showed comparable activity to donepezil and thus can be further researched for the treatment of Alzheimer's disease.

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缬昔洛韦治疗阿尔茨海默病的见解:计算对接研究和东莨菪碱大鼠模型。

背景:阿尔茨海默病(AD)损害老年人群的记忆和认知功能，其特征是细胞内神经原纤维缠结沉积，细胞外淀粉样斑块沉积和神经元变性。文献表明，潜伏在大脑中的病毒感染作为朊病毒，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。目的:基于单纯疱疹病毒(HSV)抗病毒药物对阿尔茨海默病等神经退行性疾病具有保护作用的假设，本研究旨在评价抗病毒药物，特别是阿昔洛韦的前药valacyclovir改善AD病理的疗效。方法:因此，我们通过计算机计算对接研究评估了阿昔洛韦对乙酰胆碱酯酶(AChE)、丁基胆碱酯酶(BuChE)和β -分泌酶1 (BACE-1)的潜在活性。这些发现在东莨菪碱诱导的大鼠体内认知损伤中得到了进一步的评价。对阿昔洛韦的前药valacyclovir进行了两剂口服(100mg /kg和150mg /kg)试验。结果:遗传优化配体对接评分和适应度评分与多奈哌齐相当。伐昔洛韦改善了神经行为指标。结论:伐昔洛韦与多奈哌齐具有相当的活性，可进一步研究其对阿尔茨海默病的治疗作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current neurovascular research 医学-临床神经学

CiteScore

3.80

自引率

9.50%

发文量

审稿时长

3 months

期刊介绍： Current Neurovascular Research provides a cross platform for the publication of scientifically rigorous research that addresses disease mechanisms of both neuronal and vascular origins in neuroscience. The journal serves as an international forum publishing novel and original work as well as timely neuroscience research articles, full-length/mini reviews in the disciplines of cell developmental disorders, plasticity, and degeneration that bridges the gap between basic science research and clinical discovery. Current Neurovascular Research emphasizes the elucidation of disease mechanisms, both cellular and molecular, which can impact the development of unique therapeutic strategies for neuronal and vascular disorders.