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

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.

Vitamin D3 supplementation ameliorates cognitive impairment and alters neurodegenerative and inflammatory markers in scopolamine induced rat model.

A multifaceted approach can be effective for the treatment of dementia including the most common form, Alzheimer's disease (AD). However, currently, it involves only symptomatic treatment with cholinergic drugs. Beneficial effects of high Vitamin D3 levels or its intake in the prevention and treatment of cognitive disorders have been reported. Thus, the present study examined the preventive effect of Vitamin D3 (Calcitriol) supplementation on cognitive impairment and evaluated its impact on the accumulation or degradation of Aß plaques. A single intraperitoneal injection of scopolamine was used to induce cognitive impairment in rats. Treatment of Vitamin D3 was provided for 21 days after the injection. Various behavioral parameters like learning, spatial memory and exploratory behavior, biochemical alterations in the brain homogenate and histology of the hippocampus were investigated. Our results indicated that scopolamine-induced rats depicted cognitive deficits with high Aß levels and hyperphosphorylated tau proteins in the brain tissue, while Vitamin D supplementation could significantly improve the cognitive status and lower these protein levels. These results were supported by the histopathological and immunohistochemical staining of the hippocampal brain region. Furthermore, mechanistic analysis depicted that Vitamin D supplementation improved the Aß protein clearance by increasing the neprilysin levels. It also reduced the accumulation of Aß plaques by lowering neuroinflammation as well as oxidative stress. The present findings indicate that Vitamin D3 supplementation can ameliorate cognitive deficits and thereby delay AD progression by increasing Aß plaque degradation, reducing inflammation and oxidative stress.

Role of Vitamin D in Amyloid clearance via LRP-1 upregulation in Alzheimer's disease: A potential therapeutic target?

Amyloid beta (Aß) deposition is considered to be one of the primary reason to trigger Alzheimer's disease (AD). Literature clearly suggests decline in Aß clearance to be accountable for progression of late onset AD as compared to augmented Aß production. There may be several pathways for Aß clearance out of which one of the major pathway is the vascular-mediated removal of Aß from the brain across the blood-brain barrier (BBB) via efflux pumps or receptors. Among Aß scavenger receptors, low density lipoprotein receptor related protein (LRP-1) has been most extensively studied. LRP-1, is highly expressed in neurons and located on abluminal side of the brain capillaries whose expression decreases in AD patients which give rise to increased cerebral Aß deposition. Recent evidences reveal that post 1,25-(OH)2D3 treatment, LRP1 expression increases significantly for both in-vivo and in-vitro studies, since Vitamin D receptors (VDR) are broadly expressed in brain. Biological actions of Vitamin D are mediated via its nuclear hormone receptor vitamin D receptor (VDR) and is found to regulate many genes. Several lines of evidence suggest that VDR deficiency/inhibition can be a potential risk factor for AD and sufficient Vitamin D supplementation is beneficial to prevent AD onset/pathology or slow down the progression of disease. The present review establishes a strong correlation between Vitamin D and LRP-1 and their possible involvement in Aß clearance and thereby emerging as new therapeutic target.

Safety and Toxicological Considerations of Nanomedicines: The Future Directions.

BACKGROUND: Nanomedicine, an emerging nanotechnology, imparts special biological features due to its quantum size and is a promising candidate for targeted drug delivery. At present, in spite of its novel applications in medical sciences, certain existing gaps still need to be addressed such as fate of nanoparticles and its toxicity assessment on human health. Behaviour of the entities post human body exposure and its deposition up to certain extent are some of the crucial factors to be considered for a successful treatment approach. Also, safety evaluation applicable for nanomedicine would be drastically different from bulk of drugs due to variation in size and they may respond differently depending upon their property. Due to inadequacy of data, multidisciplinary studies are being encouraged to understand toxicity of nanomedicines and adopt specific testing procedures or modifications in nanomaterials for safe design of nanomedicines. The current review offers a comprehensive understanding on the pressing need of toxicological assessment of nanomedicines, underlying challenges, future prospects followed by regulatory aspects. In a nutshell, the present review aims to provide a thorough compilation and regressive analysis onto safety and toxicity considerations of nanomedicines. METHOD: Extensive review of literature was conducted from electronic databases such as Medline and EMBASE and other bibliographies. The database was searched for articles from 1974-2017 using search terms "nanomedicines, toxicological assessment, and physicochemical parameters." Various regulatory websites (USFDA, EMA, MHRA, NANoREG, NNI) were also referred regarding the current updates on regulatory framework for nanomedicine. RESULTS: Over 200 articles were identified and referred from which relevant data was selected to be included in the current review. The outcome of the review suggests the presence of existing gaps in the knowledge of toxicity assessment of nanomedicines and it also defines specific areas which should be addressed in the near future. CONCLUSION: While nanotechnology has gained immense popularity in the research industry due to its improved efficacy compared to traditional counterparts, toxicological considerations and their regulations need to be elucidated. A strategic approach towards toxicological assessment of nanomedicine within the standard set of framework will not only motivate more research on the technology but it will also stir up the conventional drug delivery system.