Title:Insights of Valacyclovir in Treatment of Alzheimer’s Disease: Computational
Docking Studies and Scopolamine Rat Model
Volume: 19
Issue: 3
Author(s): Parmi Patel, Khushboo Faldu, Ankit Borisa, Hardik Bhatt and Jigna Shah*
Affiliation:
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
Keywords:
Alzheimer’s disease, valacyclovir, acetylcholinesterase, butyrylcholinesterase, beta-secretase 1, phosphorylated tau, amyloid-beta 1-42, disease-modifying activity.
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.
