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CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Systematic Review Article

Foresee Novel Targets for Alzheimer’s Disease by Investigating Repurposed Drugs

Author(s): Kritie Agarwal, Deepshikha Pande Katare and Ruchi Jakhmola-Mani*

Volume 22, Issue 8, 2023

Published on: 27 September, 2022

Page: [1209 - 1231] Pages: 23

DOI: 10.2174/1871527321666220622162622

Price: $65

Abstract

Background: Alzheimer’s Disease (AD) is the most rampant neurodegenerative disorder which has caused havoc worldwide. More than a century has passed since the first case of AD was reported, but still, no stable treatment is known to humanity. The available medications only provide temporary relief and are not a cure for the disease. The hunt for advanced techniques in drug development has paved the way for drug repurposing, i.e., repositioning or reutilizing drugs as an innovative approach.

Methodology: Several drugs which were repurposed for AD were collected by following PRISMA 2020 systemic review. Databases like PubMed, ScienceDirect, JSTOR, and SciELO were used for data extraction. Further, the Drugbank database was used to download all the identified drugs. Later, the Swiss Target Prediction tool was used to identify protein receptors for these drugs and the biological pathway followed by them.

Results: Drugs like Zileuton, Salbutamol, Baricitinib, Carmustine, Paclitaxel, and Nilotinib were observed to be involved in regulation of neurotransmitters. Similarly, Metformin, Liraglutide, UDCA, and Bexarotene are involved in protein kinase cascades which also is one of the prime processes in metabolic disorders like AD. Furthermore, drugs like Rosiglitazone, Pioglitazone, and Lonafarnib are involved in interleukin-3 biosynthetic processes, which is again one of the most important processes studied in AD treatment.

Conclusion: The study concluded that the reviewed drugs that follow similar biological and molecular processes could be repurposed for AD if chosen judiciously with current medications and thus, drug repurposing is a promising approach that can be utilized to find a cure for AD within a brief time and fewer resources compared to de novo drug synthesis. Although certain loopholes still need to be worked upon, the technique has great prospects. Furthermore, in silico methods can be utilized to justify the findings and identify the best drug candidate.

Keywords: Alzheimer’s disease, drug repurposing, neurotransmitter regulation, IL-3 regulation, kinase cascades, drugs.

Graphical Abstract
[1]
Kumar S, Chowdhury S, Kumar S. In silico repurposing of antipsychotic drugs for AD. BMC Neurosci 2017; 18(1): 1-16.
[http://dx.doi.org/10.1186/s12868-017-0394-8] [PMID: 28049513]
[2]
Bauzon J, Lee G, Cummings J. Repurposed agents in the Alzheimer’s disease drug development pipeline. Alzheimers Res Ther 2020; 12(1): 98.
[http://dx.doi.org/10.1186/s13195-020-00662-x] [PMID: 32807237]
[3]
Venkatachalam S, Jaiswal A, De A, Vijayakumar RK. Repurposing drugs for management of Alzheimer disease. Res J Pharm Technol 2019; 12(6): 3078-88.
[4]
Alzheimer Association. 2021. https://www.alz.org/in/dementia-alzheimers-en.asp#about [Assessed on june 13th, 2022]
[5]
Panza F, Lozupone M, Solfrizzi V, Watling M, Imbimbo BP. Time to test antibacterial therapy in Alzheimer’s disease. Brain 2019; 142(10): 2905-29.
[http://dx.doi.org/10.1093/brain/awz244] [PMID: 31532495]
[6]
Zvěřová M. Clinical aspects of Alzheimer’s disease. Clin Biochem 2019; 72: 3-6.
[http://dx.doi.org/10.1016/j.clinbiochem.2019.04.015] [PMID: 31034802]
[7]
Zanetti O, Solerte SB, Cantoni F. Life expectancy in Alzheimer’s Disease (AD). Arch Gerontol Geriatr 2009; 49 (Suppl. 1): 237-43.
[http://dx.doi.org/10.1016/j.archger.2009.09.035] [PMID: 19836639]
[8]
Kametani F, Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in AD. Front Neurosci 2018; 12: 25.
[http://dx.doi.org/10.3389/fnins.2018.00025] [PMID: 29440986]
[9]
Liu PP, Xie Y, Meng XY, Kang JS. History and progress of hypotheses and clinical trials for AD. Signal Transduct Target Ther 2019; 4(1): 1-22.
[10]
Fulop T, Witkowski JM, Bourgade K, et al. Can an infection hypothesis explain the beta amyloid hypothesis of AD? Front Aging Neurosci 2018; 10: 224.
[http://dx.doi.org/10.3389/fnagi.2018.00224] [PMID: 30087609]
[11]
Saxena U. Bioenergetics breakdown in Alzheimer’s disease: Targets For New Therapies. Int J Physiol Pathophysiol Pharmacol 2011; 3(2): 133-9.
[PMID: 21760971]
[12]
Du X, Wang X, Geng M. AD hypothesis and related therapies. Transl Neurodegener 2018; 7(1): 1-7.
[http://dx.doi.org/10.1186/s40035-018-0107-y]
[13]
Hampel H, Mesulam MM, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 2018; 141(7): 1917-33.
[http://dx.doi.org/10.1093/brain/awy132] [PMID: 29850777]
[14]
Hernández MCR, Rodríguez MH, Wejebe JEM, Basurto JC. Involvement of free radicals in the development and progression of Alzheimer’s disease. Free Radicals and Diseases 2016; p. 215.
[15]
Jakhmola-Mani R, Islam A, Katare DP. Liver-brain axis in sporadic Alzheimer’s disease: Role of ten signature genes in a mouse model. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) 2021; 20(9): 871-5.
[16]
Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement 2018; 14(12): 1602-14.
[http://dx.doi.org/10.1016/j.jalz.2018.06.3040] [PMID: 30314800]
[17]
Atri A. Current and future treatments in AD. Semin Neurol 2019; 39(2): 227-40.
[http://dx.doi.org/10.1055/s-0039-1678581] [PMID: 30925615]
[18]
Sharma K. Cholinesterase inhibitors as Alzheimer’s therapeutics (Review). Mol Med Rep 2019; 20(2): 1479-87.
[PMID: 31257471]
[19]
Marasco RA. Current and evolving treatment strategies for the Alzheimer disease continuum. Am J Manag Care 2020; 26(8) (Suppl.): S167-76.
[PMID: 32840330]
[20]
Matsunaga S, Kishi T, Nomura I, et al. The efficacy and safety of memantine for the treatment of Alzheimer’s disease. Expert Opin Drug Saf 2018; 17(10): 1053-61.
[http://dx.doi.org/10.1080/14740338.2018.1524870] [PMID: 30222469]
[21]
Kuns B, Rosani A, Varghese D. Memantine. Treasure Island, FL: StatPearls Publishers 2021.
[22]
Park K. A review of computational drug repurposing. Transl Clin Pharmacol 2019; 27(2): 59-63.
[http://dx.doi.org/10.12793/tcp.2019.27.2.59] [PMID: 32055582]
[23]
Yarchoan M, Arnold SE. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 2014; 63(7): 2253-61.
[http://dx.doi.org/10.2337/db14-0287] [PMID: 24931035]
[24]
Femminella GD, Frangou E, Love SB, et al. Evaluating the effects of the novel GLP-1 analogue liraglutide in AD: Study protocol for a randomised controlled trial (ELAD study). Trials 2019; 20(1): 1-10.
[http://dx.doi.org/10.1186/s13063-019-3259-x] [PMID: 30606236]
[25]
Koenig AM, Mechanic-Hamilton D, Xie SX, et al. Effects of the insulin sensitizer metformin in AD: Pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord 2017; 31(2): 107-13.
[http://dx.doi.org/10.1097/WAD.0000000000000202] [PMID: 28538088]
[26]
Gao C, Hölscher C, Liu Y, Li L. GSK3: A key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease. Rev in the Neurosci 2011; 23(1): 1-11.
[27]
McClean PL, Parthsarathy V, Faivre E, Hölscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 2011; 31(17): 6587-94.
[http://dx.doi.org/10.1523/JNEUROSCI.0529-11.2011] [PMID: 21525299]
[28]
Bell SM, Barnes K, Clemmens H, et al. Ursodeoxycholic acid improves mitochondrial function and redistributes Drp1 in fibroblasts from patients with either sporadic or familial AD. J Mol Biol 2018; 430(21): 3942-53.
[http://dx.doi.org/10.1016/j.jmb.2018.08.019] [PMID: 30171839]
[29]
Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G. Mitochondrial dysfunction is a trigger of AD pathophysiology. Biochimica et Biophysica Acta (BBA)-. Molecular Basis of Disease 1802; (1): 2-10.
[http://dx.doi.org/10.1016/j.bbadis.2009.10.006]
[30]
Ganguli M. A reduced risk of AD in those who survive cancer. 2012; p. e1662.
[31]
Potter H, Woodcock JH, Boyd TD, et al. Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer’s disease. Alzheimers Dement 2021; 7(1): e12158.
[http://dx.doi.org/10.1002/trc2.12158] [PMID: 33778150]
[32]
Turner RS, Hebron ML, Lawler A, et al. Nilotinib effects on safety, tolerability, and biomarkers in AD. Ann Neurol 2020; 88(1): 183-94.
[http://dx.doi.org/10.1002/ana.25775] [PMID: 32468646]
[33]
Hernandez I, Luna G, Rauch JN, et al. A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci Transl Med 2019; 11(485): eaat3005.
[http://dx.doi.org/10.1126/scitranslmed.aat3005] [PMID: 30918111]
[34]
Tousi B. The emerging role of bexarotene in the treatment of Alzheimer’s disease: Current evidence. Neuropsychiatr Dis Treat 2015; 11: 311-5.
[http://dx.doi.org/10.2147/NDT.S61309] [PMID: 25709453]
[35]
Shemesh OA, Spira ME. Rescue of neurons from undergoing hallmark tau-induced Alzheimer’s disease cell pathologies by the antimitotic drug paclitaxel. Neurobiol Dis 2011; 43(1): 163-75.
[http://dx.doi.org/10.1016/j.nbd.2011.03.008] [PMID: 21406229]
[36]
Hayes CD, Dey D, Palavicini JP, et al. Striking reduction of amyloid plaque burden in an Alzheimer’s mouse model after chronic administration of carmustine. BMC Med 2013; 11(1): 81.
[http://dx.doi.org/10.1186/1741-7015-11-81] [PMID: 23531149]
[37]
Weintraub A. AI uncovers Eli Lilly’s rheumatoid arthritis drug olumiant as potential Alzheimer’s treatment 2021.https://www.fiercebiotech.com/research/ai-uncovers-eli-lilly-s-rheumatoid-arthritis-drug-olumiant-as-potential-alzheimer-s
[39]
Townsend DJ, Mala B, Hughes E, et al. Circular dichroism spectroscopy identifies the#-adrenoceptor agonist salbutamol as a direct inhibitor of tau filament formation in vitro. ACS Chem Neurosci 2020; 11(14): 2104-16.
[40]
Silva BC, de Miranda AS, Rodrigues FG, et al. The 5-Lipoxygenase (5-LOX) inhibitor zileuton reduces inflammation and infarct size with improvement in neurological outcome following cerebral ischemia. Curr Neurovasc Res 2015; 12(4): 398-403.
[http://dx.doi.org/10.2174/1567202612666150812150606] [PMID: 26265153]
[41]
Di Meco A, Lauretti E, Vagnozzi AN, Praticò D. Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer’s disease mice. Neurobiol Aging 2014; 35(11): 2458-64.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.05.016] [PMID: 24973121]
[42]
Iqbal UH, Zeng E, Pasinetti GM. The use of antimicrobial and antiviral drugs in AD. Int J Mol Sci 2020; 21(14): 4920.
[http://dx.doi.org/10.3390/ijms21144920] [PMID: 32664669]
[43]
Patient B. An HIV Drug for Alzheimer’s?. Scientists Have Hope 2019.[https://www.beingpatient.com/hiv-drug-for-alzheimers/
[44]
Alzforum Networking for a Cure. 2021.https://www.alzforum.org/therapeutics/valacyclovir
[45]
Wishart DS, Knox C, Guo AC, et al. DrugBank: A knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res 2008; 36(Database issue) (Suppl. 1): D901-6.
[http://dx.doi.org/10.1093/nar/gkm958] [PMID: 18048412]
[46]
Gfeller D, Grosdidier A, Wirth M, Daina A, Michielin O, Zoete V. SwissTargetPrediction: A web server for target prediction of bioactive small molecules. Nucleic Acids Res 2014; 42(Web Server issue): W32-8.
[http://dx.doi.org/10.1093/nar/gku293] [PMID: 24792161]
[47]
Gasteiger E, Gattiker A, Hoogland C, Ivanyi I, Appel RD, Bairoch A. ExPASy: The proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res 2003; 31(13): 3784-8.
[http://dx.doi.org/10.1093/nar/gkg563] [PMID: 12824418]
[48]
Corcoran C, Jacobs TF. Metformin. Treasure Island, FL: StatPearls Publishers 2021.
[49]
Hermann LS. Metformin: A review of its pharmacological properties and therapeutic use. Diabete Metab 1979; 5(3): 233-45.
[PMID: 387488]
[50]
Thong KY, Gupta PS, Blann AD, Ryder REJ. The influence of age and metformin treatment status on reported gastrointestinal side effects with liraglutide treatment in type 2 diabetes. Diabetes Res Clin Pract 2015; 109(1): 124-9.
[http://dx.doi.org/10.1016/j.diabres.2015.04.009] [PMID: 25937541]
[51]
Collins L, Costello RA. Glucagon-like peptide-1 receptor agonists 2019.
[52]
Rodriguez BSQ, Correa R. Rosiglitazone. Treasure Island, FL: StatPearls Publishers 2021.
[53]
Singh G, Correa R. Pioglitazone 2019.
[54]
Achufusi TGO, Safadi AO, Mahabadi N. Ursodeoxycholic acid. Treasure Island, FL: StatPearls Publishers 2021.
[55]
Plosker GL, Robinson DM. Nilotinib. Drugs 2008; 68(4): 449-59.
[http://dx.doi.org/10.2165/00003495-200868040-00005] [PMID: 18318563]
[56]
Dhillon S. Lonafarnib: First approval. Drugs 2021; 81(2): 283-9.
[http://dx.doi.org/10.1007/s40265-020-01464-z] [PMID: 33590450]
[57]
Lowe MN, Plosker GL. Bexarotene. Am J Clin Dermatol 2000; 1(4): 245-50.
[http://dx.doi.org/10.2165/00128071-200001040-00006] [PMID: 11702369]
[58]
Farrar MC, Jacobs TF. Paclitaxel. 2019.
[59]
Henner WD, Peters WP, Eder JP, Antman K, Schnipper L, Frei E III. Pharmacokinetics and immediate effects of high-dose carmustine in man. Cancer Treat Rep 1986; 70(7): 877-80.
[PMID: 3719578]
[60]
Ahmad A, Zaheer M, Balis FJ. Baricitinib. Treasure Island, FL: StatPearls Publishers 2021.
[61]
Johnson DB, Merrell BJ, Bounds CG. Albuterol. 2018.
[62]
Bouchette D, Preuss CV. Zileuton. Treasure Island, FL: StatPearls Publishers 2021.
[63]
Adak T, Samadi A, Ünal AZ. Sabuncuoğlu S. A reappraisal on metformin. Regul Toxicol Pharmacol 2018; 92: 324-32.
[http://dx.doi.org/10.1016/j.yrtph.2017.12.023] [PMID: 29291990]
[64]
Egefjord L, Gejl M, Møller A, et al. Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer´ s disease-protocol for a controlled, randomized double-blinded trial. Brain 2012; 12: 14.
[65]
Gold M, Alderton C, Zvartau-Hind M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: Results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 2010; 30(2): 131-46.
[http://dx.doi.org/10.1159/000318845] [PMID: 20733306]
[66]
Panchal S, Parmar M. Prediction of novel therapeutic indication for rosiglitazone using its reported clinical side-effects: Drug repositioning by pharmacovigilance approach. 2017.
[67]
Galimberti D, Scarpini E. Pioglitazone for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 2017; 26(1): 97-101.
[http://dx.doi.org/10.1080/13543784.2017.1265504] [PMID: 27885860]
[68]
Saunders AM, Burns DK, Gottschalk WK. Reassessment of pioglitazone for Alzheimer’s disease. Front Neurosci 2021; 15: 666958.
[http://dx.doi.org/10.3389/fnins.2021.666958] [PMID: 34220427]
[69]
Turner RS, Hebron ML, Lawler A, et al. Nilotinib effects on safety, tolerability, and biomarkers in Alzheimer’s disease. Ann Neurol 2020; 88(1): 183-94.
[http://dx.doi.org/10.1002/ana.25775] [PMID: 32468646]
[70]
Cummings JL, Zhong K, Kinney JW, et al. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease. Alzheimers Res Ther 2016; 8(1): 4.
[http://dx.doi.org/10.1186/s13195-016-0173-2] [PMID: 26822146]

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