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

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

doi:10.2174/1567202619666220908125125

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.

Keywords: Alzheimer’s Disease, Valacyclovir, Acetylcholinesterase, Butyrylcholinesterase, Beta-secretase 1, Phosphorylated tau, Amyloid-beta 1-42, Disease-modifying activity

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[1]
Kumar A, Singh A. Ekavali. A review on Alzheimer’s disease pathophysiology and its management: An update. Pharmacol Rep  2015; 67(2): 195-203.
 [http://dx.doi.org/10.1016/j.pharep.2014.09.004] [PMID:  25712639]

[2]
McKhann GM, David SK, Howard C, et al. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement  2021; 17(3): 327-406.
 [http://dx.doi.org/10.1002/alz.12328] [PMID:  33756057]

[3]
Mukhopadhyay S, Banerjee D, Kosagisharaf JR. A primer on the evolution of aducanumab: The first antibody approved for treatment of Alzheimer’s disease. J Alzheimers Dis  2021; 83(4): 1537-52.
 [http://dx.doi.org/10.3233/JAD-215065] [PMID:  34366359]

[4]
Barber RC. The genetics of Alzheimer’s disease cairo. Scientifica  2012; 2012: 246210.
 [http://dx.doi.org/10.6064/2012/246210]

[5]
Palmqvist S, Insel PS, Stomrud E, et al. Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease. EMBO Mol Med  2019; 11(12): e11170.
 [http://dx.doi.org/10.15252/emmm.201911170]

[6]
Zetterberg H, Bendlin BB. Biomarkers for Alzheimer’s disease—Preparing for a new era of disease-modifying therapies. Mol Psychiatry  2021; 26(1): 296-308.
 [http://dx.doi.org/10.1038/s41380-020-0721-9] [PMID:  32251378]

[7]
Kammerman EM, Neumann DM, Ball MJ, Lukiw W, Hill JM. Senile plaques in Alzheimer’s diseased brains: Possible association of β-amyloid with Herpes Simplex Virus Type 1 (HSV-1) L-particles. Med Hypotheses  2006; 66(2): 294-9.
 [http://dx.doi.org/10.1016/j.mehy.2005.07.033] [PMID:  16242250]

[8]
Saldanha J, Sutton RN, Gannicliffe A, Farragher B, Itzhaki RF. Detection of HSV1 DNA by in situ hybridisation in human brain after immunosuppression. J Neurol Neurosurg Psychiatry  1986; 49(6): 613-9.
 [http://dx.doi.org/10.1136/jnnp.49.6.613] [PMID:  3016195]

[9]
Mangold CA, Szpara ML. Persistent infection with herpes simplex virus 1 and Alzheimer’s disease—A call to study how variability in both virus and host may impact disease. Viruses  2019; 11(10): 96.

[10]
De Chiara G, Piacentini R, Fabiani M, et al. Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice. PLoS Pathog  2019; 15(3): e1007617.
 [http://dx.doi.org/10.1371/journal.ppat.1007617] [PMID:  30870531]

[11]
Lövheim H, Gilthorpe J, Adolfsson R, Nilsson LG, Elgh F. Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement  2015; 11(6): 593-9.
 [http://dx.doi.org/10.1016/j.jalz.2014.04.522] [PMID:  25043910]

[12]
Piacentini R, Li Puma DD, Ripoli C, et al. Herpes simplex virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-β protein accumulation. Sci Rep  2015; 5(1): 1-14.

[13]
Faldu KG, Shah JS, Patel SS. Anti-viral agents in neurodegenerative disorders: New paradigm for targeting Alzheimer’s disease. Recent Pat Antiinfect Drug Discov  2015; 10(2): 76-83.
 [http://dx.doi.org/10.2174/1574891x10666150509193236]

[14]
Harris SA, Harris EA. Molecular mechanisms for herpes simplex virus type 1 pathogenesis in Alzheimer’s disease. Front Aging Neurosci  2018; 10(MAR): 48.
 [http://dx.doi.org/10.3389/fnagi.2018.00048] [PMID:  29559905]

[15]
Valyi NT, Dermody TS. Role of oxidative damage in the pathogenesis of viral infections of the nervous system. Histol Histopathol  2005; 20(3): 957-67.
 [PMID:  15944946]

[16]
Barai P, Raval N, Acharya S, Borisa A, Bhatt H, Acharya N. Neuroprotective effects of bergenin in Alzheimer’s disease: Investigation through molecular docking, in vitro and in vivo studies. Behav Brain Res  2019; 356: 18-40.
 [http://dx.doi.org/10.1016/j.bbr.2018.08.010] [PMID:  30118774]

[17]
Alikatte KL, Akondi BR, Yerragunta VG, Veerareddy PR, Palle S. Antiamnesic activity of Syzygium cumini against scopolamine induced spatial memory impairments in rats. Brain Dev  2012; 34(10): 844-51.
 [http://dx.doi.org/10.1016/j.braindev.2012.02.008] [PMID:  22475379]

[18]
Deb D, Bairy KL, Nayak V, Rao M. Comparative effect of lisinopril and fosinopril in mitigating learning and memory deficit in scopolamine-induced amnesic rats. Adv Pharmacol Sci  2015; 2015: 521718.
 [http://dx.doi.org/10.1155/2015/521718]

[19]
Farswan SM, Bhagwan SS, Singh V, Rawal S, Bajaj H, Bisht A. Memory enhancing effect of mirtazapine with ascorbic acid on scopolamine induced amnesia in rats. Guru Drone J Pharm Res  2013; 1(1): 29-38.

[20]
Brandeis R, Brandys Y, Yehuda S. The use of the Morris Water Maze in the study of memory and learning. Int J Neurosci  1989; 48(1-2): 29-69.
 [http://dx.doi.org/10.3109/00207458909002151] [PMID:  2684886]

[21]
Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc  2006; 1(2): 848-58.
 [http://dx.doi.org/10.1038/nprot.2006.116] [PMID:  17406317]

[22]
Bromley BK, Deng Y, Song W. Morris water maze test for learning and memory deficits in Alzheimer’s disease model mice. J Vis Exp  2011; (53): 2920.
 [http://dx.doi.org/10.3791/2920]

[23]
Conrad CD, Lupien SJ, Thanasoulis LC, McEwen BS. The effects of type I and type II corticosteroid receptor agonists on exploratory behavior and spatial memory in the Y-maze. Brain Res  1997; 759(1): 76-83.
 [http://dx.doi.org/10.1016/S0006-8993(97)00236-9] [PMID:  9219865]

[24]
Shah JS, Faldu KG, Patel SS. Celastrus paniculatus oil ameliorates synaptic plasticity in a rat model of attention deficit hyperactivity disorder. Asian Pac J Trop Biomed  2021; 11(3): 105.
 [http://dx.doi.org/10.4103/2221-1691.306690]

[25]
Curzon P, Rustay NR, Browman KE. Cued and Contextual Fear Conditioning for Rodents.   2009; pp. 19-37. Available from: https://www.ncbi.nlm.nih.gov/books/NBK5223/

[26]
Dhanasekaran S, Perumal P, Palayan M. In-vitro screening for acetylcholinesterase enzyme inhibition potential and antioxidant activity of extracts of Ipomoea aquatica Forsk: Therapeutic lead for Alzheimer’s disease. J Appl Pharm Sci  2015; 5(2): 012-6.
 [http://dx.doi.org/10.7324/JAPS.2015.50203]

[27]
Singh A, Kumar A. Comparative analysis of intrahippocampal amyloid beta (1-42) intracerbroventricular streptozotocin models of Alzheimer’s disease: Possible behavioral, biochemical, mitochondrial, cellular andhistopathological evidences. J Alzheimers Dis Park  2016; 6(1): 1-7.

[28]
Birman S. Determination of acetylcholinesterase activity by a new chemiluminescence assay with the natural substrate. Biochem J  1985; 225(3): 825-8.
 [http://dx.doi.org/10.1042/bj2250825]

[29]
Zaki HF, Abd-El-Fattah MA, Attia AS. Naringenin protects against scopolamine-induced dementia in rats. Bull Fac Pharm Cairo Univ  2014; 52(1): 15-25.
 [http://dx.doi.org/10.1016/j.bfopcu.2013.11.001]

[30]
Feldman AT, Wolfe D. Tissue processing and hematoxylin and eosin staining. Methods Mol Biol  2014; 1180: 31-43.
 [http://dx.doi.org/10.1007/978-1-4939-1050-2_3] [PMID:  25015141]

[31]
WHO. An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection WHO.  2008. Available from: http://www.who.int/bulletin/volumes/86/10/07-046128/en/

[32]
Gebhardt BM, Varnell ED, Kaufman HE. Inhibition of cyclooxygenase 2 synthesis suppresses herpes simplex virus type 1 reactivation. J Ocul Pharmacol Ther  2005; 21(2): 114-20.
 [http://dx.doi.org/10.1089/jop.2005.21.114] [PMID:  15857277]

[33]
Pilotto A, Cristillo V, Piccinelli SC, et al. Long-term neurological manifestations of COVID-19: Prevalence and predictive factors. Neurol Sci  2021; 42(12): 4903-7.
 [http://dx.doi.org/10.1007/s10072-021-05586-4]

[34]
Schnier C, Wilkinson T, Akbari A, et al. The Secure Anonymised Information Linkage Databank Dementia E-Cohort (SAIL-DeC). Int J Popul Data Sci  2020; 5(1): 1121.

[35]
Zilli EM, O’Donnell A, Salinas J, et al. Herpes Labialis, Chlamydophila pneumoniae, Helicobacter pylori, and Cytomegalovirus infections and risk of dementia: The Framingham heart study. J Alzheimers Dis  2021; 82(2): 593-605.
 [http://dx.doi.org/10.3233/JAD-200957] [PMID:  34057145]

[36]
Linard M, Bezin J, Hucteau E, et al. Antiherpetic drugs: A potential way to prevent Alzheimer’s disease? Alzheimers Res Ther  2022; 14(1): 3.
 [http://dx.doi.org/10.1186/s13195-021-00950-0] [PMID:  34996520]

[37]
Lopatko LK, Hemmingsson ES, Weidung B, et al. Herpesvirus infections, antiviral treatment, and the risk of dementia—A registry-based cohort study in Sweden. Alzheimer’s Dement Transl Res Clin Interv  2021; 7(1): e12119.

[38]
Hemmingsson ES, Hjelmare E, Weidung B, et al. Antiviral treatment associated with reduced risk of clinical Alzheimer’s disease-A nested case-control study. Alzheimers Dement  2021; 7(1): e12187.
 [http://dx.doi.org/10.1002/trc2.12187]

[39]
Devanand DP, Andrews H, Kreisl WC, et al. Antiviral therapy: Valacyclovir Treatment of Alzheimer’s Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial. BMJ Open  2020; 10(2): e032112.
 [http://dx.doi.org/10.1136/bmjopen-2019-032112] [PMID:  32034019]

[40]
Weidung B, Hemmingsson ES, Olsson J, et al. VALZ-Pilot: High-dose valacyclovir treatment in patients with early-stage Alzheimer’s disease. Alzheimer’s Dement Transl Res Clin Interv  2022; 8(1): e12264.

[41]
Cheon SY, Koo BN, Kim SY, Kam EH, Nam J, Kim EJ. Scopolamine promotes neuroinflammation and delirium-like neuropsychiatric disorder in mice. Sci Rep  2021; 11(1): 8376.
 [http://dx.doi.org/10.1038/s41598-021-87790-y]

[42]
Blokland A. Cholinergic models of memory impairment in animals and man: scopolamine vs. biperiden. Behav Pharmacol  2022; 33(4): 231-7.
 [http://dx.doi.org/10.1097/FBP.0000000000000670] [PMID:  35621168]

[43]
Farooqui AA. Potential treatment strategies of dementia with ayurvedic medicines. Mol Mech Dement  2019; 2019: 287-328.
 [http://dx.doi.org/10.1016/B978-0-12-816347-4.00009-X]

[44]
Topuz RD, Gunduz O, Tastekin E, Karadag CH. Effects of hippocampal histone acetylation and HDAC inhibition on spatial learning and memory in the Morris water maze in rats. Fundam Clin Pharmacol  2020; 34(2): 222-8.
 [http://dx.doi.org/10.1111/fcp.12512] [PMID:  31617237]

[45]
Ademosun AO, Adebayo AA, Popoola TV, Oboh G. Shaddock (Citrus maxima) peels extract restores cognitive function, cholinergic and purinergic enzyme systems in scopolamine-induced amnesic rats. Drug Chem Toxicol  2020; 45(3): 1073-80.
 [http://dx.doi.org/10.1080/01480545.2020.1808668] [PMID:  32847424]

[46]
Falsafi SK, Deli A, Höger H, Pollak A, Lubec G. Scopolamine administration modulates muscarinic, nicotinic and NMDA receptor systems. PLoS One  2012; 7(2): e32082.
 [http://dx.doi.org/10.1371/journal.pone.0032082] [PMID:  22384146]

[47]
Hammond R, Tull LE, Stackman RW. On the delay-dependent involvement of the hippocampus in object recognition memory. Neurobiol Learn Mem  2004; 82(1): 26-34.
 [http://dx.doi.org/10.1016/j.nlm.2004.03.005] [PMID:  15183168]

[48]
Plater MJ, Hussain H, Ahmad S, et al. Attenuation of scopolamine-induced amnesia via cholinergic modulation in mice by synthetic curcumin analogs. Mol  2022; 27: 2468.

[49]
Ahlenius S, Ericson E. Scopolamine does not restore normal conditioned avoidance performance in raclopride-treated rats. J Neural Transm (Vienna)  2001; 108(4): 415-30.
 [http://dx.doi.org/10.1007/s007020170063] [PMID:  11475009]

[50]
Khurana K, Kumar M, Bansal N. Lacidipine prevents scopolamine-induced memory impairment by reducing brain oxido-nitrosative stress in mice. Neurotox Res  2021; 39(4): 1087-102.
 [http://dx.doi.org/10.1007/s12640-021-00346-w] [PMID:  33721210]

[51]
Tang KS. The cellular and molecular processes associated with scopolamine-induced memory deficit: A model of Alzheimer’s biomarkers. Life Sci  2019; 233: 116695.
 [http://dx.doi.org/10.1016/j.lfs.2019.116695] [PMID:  31351082]

[52]
Yun YJ, Park BH, Hou J, Oh JP, Han JH, Kim SC. Ginsenoside F1 Protects the brain against amyloid beta-induced toxicity by regulating IDE and NEP. Life  2022; 12(1): 58.
 [http://dx.doi.org/10.3390/life12010058] [PMID:  35054451]

[53]
Abdel LMS, Abady MMA, Saleh SR, Abdel MN, Ghareeb DA. Effect of berberine and ipriflavone mixture against scopolamine-induced Alzheimer-like disease. Int J Pharm Phytopharm Res  2019; 9(3): 48-63.

[54]
Torres AN, O’Keefe JH, O’Keefe EL, Isaacson R, Small G. Therapeutic potential of TNF-α inhibition for Alzheimer’s disease prevention. J Alzheimers Dis  2020; 78(2): 619-26.
 [http://dx.doi.org/10.3233/JAD-200711] [PMID:  33016914]

[55]
Jha NK, Jha SK, Kar R, Nand P, Swati K, Goswami VK. Nuclear factor‐kappa β as a therapeutic target for Alzheimer’s disease. J Neurochem  2019; 150(2): 113-37.
 [http://dx.doi.org/10.1111/jnc.14687] [PMID:  30802950]

[56]
Godbout JP, Johnson RW. Interleukin-6 in the aging brain. J Neuroimmunol  2004; 147(1-2): 141-4.
 [http://dx.doi.org/10.1016/j.jneuroim.2003.10.031] [PMID:  14741447]

[57]
Schneider H, Pitossi F, Balschun D, Wagner A, Del Rey A, Besedovsky HO. A neuromodulatory role of interleukin-1β in the hippocampus. Proc Natl Acad Sci USA  1998; 95(13): 7778-83.
 [http://dx.doi.org/10.1073/pnas.95.13.7778] [PMID:  9636227]

[58]
Mastrangelo MA, Sudol KL, Narrow WC, Bowers WJ. Interferon-γ differentially affects Alzheimer’s disease pathologies and induces neurogenesis in triple transgenic-AD mice. Am J Pathol  2009; 175(5): 2076-88.
 [http://dx.doi.org/10.2353/ajpath.2009.090059]

[59]
Llorens MM, Rábano A, Ávila J. The ever-changing morphology of hippocampal granule neurons in physiology and pathology. Front Neurosci  2016; 9: 526.

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