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image of Transforming Alzheimer's Treatment: Unveiling New Potential with Drug Repurposing Strategies

Abstract

Alzheimer's disease (AD) remains a significant challenge in neurology, marked by progressive cognitive decline and neurodegeneration. Despite extensive research efforts, effective treatments are still lacking. Traditional drug discovery is often slow and costly, frequently resulting in limited success. Drug repurposing, which identifies new therapeutic uses for existing medications, has emerged as a promising approach to expedite AD treatment development. This review examines the potential of drug repurposing to transform AD therapy by utilizing the established safety profiles and known mechanisms of current drugs. We explore various repurposed drugs under investigation for AD, originally intended for cardiovascular, metabolic, and psychiatric conditions. Detailed discussions include how these drugs provide neuroprotective benefits by inhibiting amyloid-beta aggregation, reducing tau phosphorylation, and modulating neuroinflammation. Additionally, we emphasize the benefits of drug repurposing, such as shortened development timelines, lower costs, and increased chances of clinical success. By integrating current research findings, this review offers a thorough overview of the most promising repurposed drug candidates and their potential impact on AD treatment strategies. It stresses the importance of innovative approaches in AD research and calls for greater investment in drug repurposing initiatives. Through these strategies, we aim to accelerate the availability of effective treatments, providing renewed hope and a brighter future for those affected by this devastating disease.

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/content/journals/cmc/10.2174/0109298673341391241231054936
2024-01-23
2025-06-24
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References

  1. Jahn H. Memory loss in Alzheimer’s disease. Dialogues Clin. Neurosci. 2013 15 4 445 454 10.31887/DCNS.2013.15.4/hjahn 24459411
    [Google Scholar]
  2. Corbett A. Ballard C. Information provision services in dementia care. Int. J. Older People Nurs. 2011 6 3 217 226 10.1111/j.1748‑3743.2011.00289.x 21884487
    [Google Scholar]
  3. Ballard C. Aarsland D. Cummings J. O’Brien J. Mills R. Molinuevo J.L. Fladby T. Williams G. Doherty P. Corbett A. Sultana J. Drug repositioning and repurposing for Alzheimer disease. Nat. Rev. Neurol. 2020 16 12 661 673 10.1038/s41582‑020‑0397‑4 32939050
    [Google Scholar]
  4. Ballard C. Corbett A. Jones E.L. Dementia: Challenges and promising developments. Lancet Neurol. 2011 10 1 7 9 10.1016/S1474‑4422(10)70304‑5 21163436
    [Google Scholar]
  5. Hu Y. Yu K. Wang G. Zhang D. Shi C. Ding Y. Hong D. Zhang D. He H. Sun L. Zheng J.N. Sun S. Qian F. Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell. Biochem. Pharmacol. 2018 150 280 292 10.1016/j.bcp.2018.02.023 29475060
    [Google Scholar]
  6. Ballard C. Corbett A. Sharp S. Aligning the evidence with practice: NICE guidelines for drug treatment of Alzheimer’s disease. Expert Rev. Neurother. 2011 11 3 327 329 10.1586/ern.11.13 21375436
    [Google Scholar]
  7. Wimo A. Guerchet M. Ali G.C. Wu Y.T. Prina A.M. Winblad B. Jönsson L. Liu Z. Prince M. The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement. 2017 13 1 1 7 10.1016/j.jalz.2016.07.150 27583652
    [Google Scholar]
  8. An Y. Varma V.R. Varma S. Casanova R. Dammer E. Pletnikova O. Chia C.W. Egan J.M. Ferrucci L. Troncoso J. Levey A.I. Lah J. Seyfried N.T. Legido-Quigley C. O’Brien R. Thambisetty M. Evidence for brain glucose dysregulation in Alzheimer’s disease. Alzheimers Dement. 2018 14 3 318 329 10.1016/j.jalz.2017.09.011 29055815
    [Google Scholar]
  9. Kwok M.K. Lin S.L. Schooling C.M. Re-thinking Alzheimer’s disease therapeutic targets using gene-based tests. EBioMedicine 2018 37 461 470 10.1016/j.ebiom.2018.10.001 30314892
    [Google Scholar]
  10. Chan Y.H. Schooling C.M. Zhao J.V. Yeung S.L.A. Hai J.J. Thomas G.N. Cheng K.K. Jiang C.Q. Wong Y.K. Au K.W. Tang C.S. Cheung C.Y.Y. Xu A. Sham P.C. Lam T.H. Lam K.S.L. Tse H.F. Mendelian randomization analysis of vitamin D in the secondary prevention of hypertensive-diabetic subjects: Role of facilitating blood pressure control. Genes Nutr. 2022 17 1 1 10.1186/s12263‑022‑00704‑z 35093020
    [Google Scholar]
  11. Director-General addresses G8 dementia summit. Available from: https://www.who.int/director-general/speeches/detail/who-director-general-addresses-g8-dementia-summit
  12. DeTure M.A. Dickson D.W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegener. 2019 14 1 32 10.1186/s13024‑019‑0333‑5 31375134
    [Google Scholar]
  13. Murray M.E. Graff-Radford N.R. Ross O.A. Petersen R.C. Duara R. Dickson D.W. Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: A retrospective study. Lancet Neurol. 2011 10 9 785 796 10.1016/S1474‑4422(11)70156‑9 21802369
    [Google Scholar]
  14. Fan L. Mao C. Hu X. Zhang S. Yang Z. Hu Z. Sun H. Fan Y. Dong Y. Yang J. Shi C. Xu Y. New insights into the pathogenesis of alzheimer’s disease. Front. Neurol. 2020 10 1312 10.3389/fneur.2019.01312 31998208
    [Google Scholar]
  15. Karran E Mercken M FGF23 and fetuin-a interaction in the liver and in the circulation. Int. J. Biol. Sci. 2018 14 5 586 598
    [Google Scholar]
  16. Ittner L.M. Ke Y.D. Delerue F. Bi M. Gladbach A. van Eersel J. Wölfing H. Chieng B.C. Christie M.J. Napier I.A. Eckert A. Staufenbiel M. Hardeman E. Götz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 2010 142 3 387 397 10.1016/j.cell.2010.06.036 20655099
    [Google Scholar]
  17. Rajmohan R. Reddy P.H. Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of alzheimer’s disease neurons. J. Alzheimers Dis. 2017 57 4 975 999 10.3233/JAD‑160612 27567878
    [Google Scholar]
  18. Chen G. Xu T. Yan Y. Zhou Y. Jiang Y. Melcher K. Xu H.E. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 2017 38 9 1205 1235 10.1038/aps.2017.28 28713158
    [Google Scholar]
  19. Mehta D. Jackson R. Paul G. Shi J. Sabbagh M. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin. Investig. Drugs 2017 26 6 735 739 10.1080/13543784.2017.1323868 28460541
    [Google Scholar]
  20. Yiannopoulou K.G. Anastasiou A.I. Zachariou V. Pelidou S.H. Reasons for failed trials of disease-modifying treatments for alzheimer disease and their contribution in recent research. Biomedicines 2019 7 4 97 10.3390/biomedicines7040097 31835422
    [Google Scholar]
  21. Tatulian S.A. Challenges and hopes for Alzheimer’s disease. Drug Discov. Today 2022 27 4 1027 1043 10.1016/j.drudis.2022.01.016 35121174
    [Google Scholar]
  22. Petersen R.C. Clinical practice. Mild cognitive impairment. N. Engl. J. Med. 2011 364 23 2227 2234 10.1056/NEJMcp0910237 21651394
    [Google Scholar]
  23. Petersen R.C. Mild cognitive impairment. Continuum 2016 22 2, Dementia 404 418 10.1212/CON.0000000000000313 27042901
    [Google Scholar]
  24. Jack C.R. Jr Albert M.S. Knopman D.S. McKhann G.M. Sperling R.A. Carrillo M.C. Thies B. Phelps C.H. Introduction to the recommendations from the national institute on aging-alzheimer’s association workgroups on diagnostic guidelines for alzheimer’s disease. Alzheimers Dement. 2011 7 3 257 262 10.1016/j.jalz.2011.03.004 21514247
    [Google Scholar]
  25. Serrano-Pozo A. Frosch M.P. Masliah E. Hyman B.T. Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2011 1 1 a006189 10.1101/cshperspect.a006189 22229116
    [Google Scholar]
  26. Panza F Lozupone M Logroscino G Imbimbo BP A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 2019 15 2 73 88 10.1038/s41582‑018‑0116‑6
    [Google Scholar]
  27. Huang L.K. Chao S.P. Hu C.J. Clinical trials of new drugs for Alzheimer disease. J. Biomed. Sci. 2020 27 1 18 10.1186/s12929‑019‑0609‑7 31906949
    [Google Scholar]
  28. Brody D.L. Holtzman D.M. Active and passive immunotherapy for neurodegenerative disorders. Annu. Rev. Neurosci. 2008 31 1 175 193 10.1146/annurev.neuro.31.060407.125529 18352830
    [Google Scholar]
  29. Long J.M. Holtzman D.M. Alzheimer disease: An update on pathobiology and treatment strategies. Cell 2019 179 2 312 339 10.1016/j.cell.2019.09.001 31564456
    [Google Scholar]
  30. Wilcock G.K. Black S.E. Hendrix S.B. Zavitz K.H. Swabb E.A. Laughlin M.A. Tarenflurbil Phase II Study investigators Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: A randomised phase II trial. Lancet Neurol. 2008 7 6 483 493 10.1016/S1474‑4422(08)70090‑5 18450517
    [Google Scholar]
  31. Salloway S Sperling R Gilman S Fox N Neurology KB A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009 73 24 2061 2070
    [Google Scholar]
  32. Athar T. Al Balushi K. Khan S.A. Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease. Mol. Biol. Rep. 2021 48 7 5629 5645 10.1007/s11033‑021‑06512‑9 34181171
    [Google Scholar]
  33. Mo J.J. Li J. Yang Z. Liu Z. Feng J.S. Efficacy and safety of anti-amyloid- β immunotherapy for Alzheimer’s disease: A systematic review and network meta-analysis. Ann. Clin. Transl. Neurol. 2017 4 12 931 942 10.1002/acn3.469 29296624
    [Google Scholar]
  34. Van Dyck CH Anti-amyloid-β monoclonal antibodies for alzheimer's disease: Pitfalls and promise. Biol. Psychiatry 2018 83 4 311 319
    [Google Scholar]
  35. Mullane K. Williams M. Alzheimer’s disease (AD) therapeutics – 1: Repeated clinical failures continue to question the amyloid hypothesis of AD and the current understanding of AD causality. Biochem. Pharmacol. 2018 158 359 375 10.1016/j.bcp.2018.09.026 30273553
    [Google Scholar]
  36. Jeremic D. Jiménez-Díaz L. Navarro-López J.D. Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: A systematic review. Ageing Res. Rev. 2021 72 101496 10.1016/j.arr.2021.101496 34687956
    [Google Scholar]
  37. Cummings J. Ritter A. Zhong K. Clinical trials for disease-modifying therapies in alzheimer’s disease: A primer, lessons learned, and a blueprint for the future. J. Alzheimers Dis. 2018 64 s1 Suppl. 1 S3 S22 10.3233/JAD‑179901 29562511
    [Google Scholar]
  38. Sirota M. Dudley J.T. Kim J. Chiang A.P. Morgan A.A. Sweet-Cordero A. Sage J. Butte A.J. Discovery and preclinical validation of drug indications using compendia of public gene expression data. Sci. Transl. Med. 2011 3 96 96ra77 10.1126/scitranslmed.3001318 21849665
    [Google Scholar]
  39. Garber K. Genentech’s Alzheimer’s antibody trial to study disease prevention. Nat. Biotechnol. 2012 30 8 731 732 10.1038/nbt0812‑731 22871696
    [Google Scholar]
  40. Godyń J. Jończyk J. Panek D. Malawska B. Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol. Rep. 2016 68 1 127 138 10.1016/j.pharep.2015.07.006 26721364
    [Google Scholar]
  41. Home. Available from: https://clinicaltrials.gov/
  42. ISRCTN Registry. Available from: https://www.isrctn.com/
  43. Corriveau R.A. Koroshetz W.J. Gladman J.T. Jeon S. Babcock D. Bennett D.A. Carmichael S.T. Dickinson S.L.J. Dickson D.W. Emr M. Fillit H. Greenberg S.M. Hutton M.L. Knopman D.S. Manly J.J. Marder K.S. Moy C.S. Phelps C.H. Scott P.A. Seeley W.W. Sieber B.A. Silverberg N.B. Sutherland M.L. Taylor A. Torborg C.L. Waddy S.P. Gubitz A.K. Holtzman D.M. Alzheimer’s disease–related dementias summit 2016: National research priorities. Neurology 2017 89 23 2381 2391 10.1212/WNL.0000000000004717 29117955
    [Google Scholar]
  44. Brown N. Cambruzzi J. Cox P.J. Davies M. Dunbar J. Plumbley D. Sellwood M.A. Sim A. Williams-Jones B.I. Zwierzyna M. Sheppard D.W. Big data in drug discovery. Prog. Med. Chem. 2018 57 1 277 356 10.1016/bs.pmch.2017.12.003 29680150
    [Google Scholar]
  45. Rudrapal M Khairnar SJ Jadhav AG Drug repurposing (DR): An emerging approach in drug discovery. Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications IntechOpen 2020
    [Google Scholar]
  46. Saraei P. Asadi I. Kakar M.A. Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: A comprehensive review of recent advances. Cancer Manag. Res. 2019 11 3295 3313 10.2147/CMAR.S200059 31114366
    [Google Scholar]
  47. Cha Y. Erez T. Reynolds I.J. Kumar D. Ross J. Koytiger G. Kusko R. Zeskind B. Risso S. Kagan E. Papapetropoulos S. Grossman I. Laifenfeld D. Drug repurposing from the perspective of pharmaceutical companies. Br. J. Pharmacol. 2018 175 2 168 180 10.1111/bph.13798 28369768
    [Google Scholar]
  48. Dubois B. Hampel H. Feldman H.H. Scheltens P. Aisen P. Andrieu S. Bakardjian H. Benali H. Bertram L. Blennow K. Broich K. Cavedo E. Crutch S. Dartigues J.F. Duyckaerts C. Epelbaum S. Frisoni G.B. Gauthier S. Genthon R. Gouw A.A. Habert M.O. Holtzman D.M. Kivipelto M. Lista S. Molinuevo J.L. O’Bryant S.E. Rabinovici G.D. Rowe C. Salloway S. Schneider L.S. Sperling R. Teichmann M. Carrillo M.C. Cummings J. Jack C.R. Jr Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer’s Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement. 2016 12 3 292 323 10.1016/j.jalz.2016.02.002 27012484
    [Google Scholar]
  49. Cummings J. Aisen P.S. DuBois B. Frölich L. Jack C.R. Jr Jones R.W. Morris J.C. Raskin J. Dowsett S.A. Scheltens P. Drug development in Alzheimer’s disease: The path to 2025. Alzheimers Res. Ther. 2016 8 1 39 10.1186/s13195‑016‑0207‑9 27646601
    [Google Scholar]
  50. Uleman J.F. Melis R.J.F. Hoekstra A.G. Olde Rikkert M.G.M. Quax R. Australian Imaging, Biomarker and Lifestyle study of Aging and Alzheimer’s Disease Neuroimaging Initiative studies Exploring the potential impact of multi-factor precision interventions in Alzheimer’s disease with system dynamics. J. Biomed. Inform. 2023 145 July 104462 10.1016/j.jbi.2023.104462 37516375
    [Google Scholar]
  51. Jourdan J.P. Bureau R. Rochais C. Dallemagne P. Drug repositioning: A brief overview. J. Pharm. Pharmacol. 2020 72 9 1145 1151 10.1111/jphp.13273 32301512
    [Google Scholar]
  52. Shoaib M. Kamal M.A. Rizvi S.M.D. Repurposed drugs as potential therapeutic candidates for the management of Alzheimer’s disease. Curr. Drug Metab. 2017 18 9 842 852 28595531
    [Google Scholar]
  53. Arbo B.D. Schimith L.E. Goulart dos Santos M. Hort M.A. Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation. Eur. J. Pharmacol. 2022 919 174800 10.1016/j.ejphar.2022.174800 35131314
    [Google Scholar]
  54. Hua Y. Dai X. Xu Y. Xing G. Liu H. Lu T. Chen Y. Zhang Y. Drug repositioning: Progress and challenges in drug discovery for various diseases. Eur. J. Med. Chem. 2022 234 114239 10.1016/j.ejmech.2022.114239 35290843
    [Google Scholar]
  55. Honig L.S. Boyd C.D. Treatment of Alzheimer’s disease: Current management and experimental therapeutics. Curr. Transl. Geriatr. Exp. Gerontol. Rep. 2013 2 3 174 181 10.1007/s13670‑013‑0056‑3 24093080
    [Google Scholar]
  56. Roach J.C. Hara J. Fridman D. Lovejoy J.C. Jade K. Heim L. Romansik R. Swietlikowski A. Phillips S. Rapozo M.K. Shay M.A. Fischer D. Funk C. Dill L. Brant-Zawadzki M. Hood L. Shankle W.R. The coaching for cognition in Alzheimer’s (COCOA) trial: Study design. Alzheimers Dement. (N. Y.) 2022 8 1 e12318 10.1002/trc2.12318 35910672
    [Google Scholar]
  57. Gouilly D Rafiq M Nogueira L Salabert AS Payoux P Péran P Beyond the amyloid cascade: An update of Alzheimer’s disease pathophysiology. Rev. Neurol. 2023
    [Google Scholar]
  58. Yiannopoulou K.G. Papageorgiou S.G. Current and future treatments in alzheimer disease: An update. J. Cent. Nerv. Syst. Dis. 2020 12 10.1177/1179573520907397 32165850
    [Google Scholar]
  59. Breijyeh Z Karaman R Muñoz-Torrero D Dembinski R. Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules 2020 25 24 5789 5789 10.3390/molecules25245789 33302541
    [Google Scholar]
  60. Arafah A. Khatoon S. Rasool I. Khan A. Rather M.A. Abujabal K.A. Faqih Y.A.H. Rashid H. Rashid S.M. Bilal Ahmad S. Alexiou A. Rehman M.U. The future of precision medicine in the cure of Alzheimer’s disease. Biomedicines 2023 11 2 335 10.3390/biomedicines11020335 36830872
    [Google Scholar]
  61. Isaacson R.S. Ganzer C.A. Hristov H. Hackett K. Caesar E. Cohen R. Kachko R. Meléndez-Cabrero J. Rahman A. Scheyer O. Hwang M.J. Berkowitz C. Hendrix S. Mureb M. Schelke M.W. Mosconi L. Seifan A. Krikorian R. The clinical practice of risk reduction for Alzheimer’s disease: A precision medicine approach. Alzheimers Dement. 2018 14 12 1663 1673 10.1016/j.jalz.2018.08.004 30446421
    [Google Scholar]
  62. Aisen P.S. Schafer K.A. Grundman M. Pfeiffer E. Sano M. Davis K.L. Farlow M.R. Jin S. Thomas R.G. Thal L.J. Alzheimer’s Disease Cooperative Study Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: A randomized controlled trial. JAMA 2003 289 21 2819 2826 10.1001/jama.289.21.2819 12783912
    [Google Scholar]
  63. Krishnamurthy N. Grimshaw A.A. Axson S.A. Choe S.H. Miller J.E. Drug repurposing: A systematic review on root causes, barriers and facilitators. BMC Health Serv. Res. 2022 22 1 970 10.1186/s12913‑022‑08272‑z 35906687
    [Google Scholar]
  64. Peron R. Vatanabe I.P. Manzine P.R. Camins A. Cominetti M.R. Alpha-secretase ADAM10 regulation: Insights into Alzheimer’s disease treatment. Pharmaceutics 2018 11 1 12
    [Google Scholar]
  65. Ali M.M. Ghouri R.G. Ans A.H. Akbar A. Toheed A. Recommendations for anti-inflammatory treatments in alzheimer’s disease: A comprehensive review of the literature. Cureus 2019 11 5 e4620 10.7759/cureus.4620 31312547
    [Google Scholar]
  66. Bauzon J. Lee G. Cummings J. Repurposed agents in the Alzheimer’s disease drug development pipeline. Alzheimers Res. Ther. 2020 12 1 98 10.1186/s13195‑020‑00662‑x 32807237
    [Google Scholar]
  67. Miculas D.C. Negru P.A. Bungau S.G. Behl T. Hassan S.S. Tit D.M. Pharmacotherapy evolution in Alzheimer’s disease: Current framework and relevant directions. Cells 2022 12 1 131 10.3390/cells12010131 36611925
    [Google Scholar]
  68. Zhang J. Zhang Y. Wang J. Xia Y. Zhang J. Chen L. Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies. Signal Transduct Target Ther 2024 9 1 1 35 10.1038/s41392‑024‑01911‑3
    [Google Scholar]
  69. Loging W. Rodriguez-Esteban R. Hill J. Freeman T. Miglietta J. Cheminformatic/bioinformatic analysis of large corporate databases: Application to drug repurposing. Drug Discov. Today Ther. Strateg. 2011 8 3-4 109 116 10.1016/j.ddstr.2011.06.004
    [Google Scholar]
  70. Parvathaneni V. Kulkarni N.S. Muth A. Gupta V. Drug repurposing: A promising tool to accelerate the drug discovery process. Drug Discov. Today 2019 24 10 2076 2085 10.1016/j.drudis.2019.06.014 31238113
    [Google Scholar]
  71. Savva K. Zachariou M. Bourdakou M.M. Dietis N. Spyrou G.M. Network-based stage-specific drug repurposing for Alzheimer’s disease. Comput. Struct. Biotechnol. J. 2022 20 1427 1438 10.1016/j.csbj.2022.03.013 35386099
    [Google Scholar]
  72. Rajput A. Thakur A. Rastogi A. Choudhury S. Kumar M. Computational identification of repurposed drugs against viruses causing epidemics and pandemics via drug-target network analysis. Comput. Biol. Med. 2021 136 104677 10.1016/j.compbiomed.2021.104677 34332351
    [Google Scholar]
  73. Ye Q. Hsieh C.Y. Yang Z. Kang Y. Chen J. Cao D. He S. Hou T. A unified drug–target interaction prediction framework based on knowledge graph and recommendation system. Nat. Commun. 2021 12 1 6775 10.1038/s41467‑021‑27137‑3 34811351
    [Google Scholar]
  74. Judge A. Garriga C. Arden N. Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients. Alzheimers Dement. 2017 3 4 612 621 10.1016/j.trci.2017.10.002
    [Google Scholar]
  75. Xu M. Lee E.M. Wen Z. Cheng Y. Huang W.K. Qian X. Tcw J. Kouznetsova J. Ogden S.C. Hammack C. Jacob F. Nguyen H.N. Itkin M. Hanna C. Shinn P. Allen C. Michael S.G. Simeonov A. Huang W. Christian K.M. Goate A. Brennand K.J. Huang R. Xia M. Ming G. Zheng W. Song H. Tang H. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat. Med. 2016 22 10 1101 1107 10.1038/nm.4184 27571349
    [Google Scholar]
  76. Williams G Gatt A Clarke E Drug repurposing for Alzheimer's disease based on transcriptional profiling of human iPSC-derived cortical neurons. Transl. Psychiatry 2019 9 1 220 220
    [Google Scholar]
  77. Killick R. Elliott C. Ribe E. Broadstock M. Ballard C. Aarsland D. Neurodegenerative disease associated pathways in brain of the triple transgenic Alzheimer’s model are reversed in vivo following two weeks peripheral administration. biorxiv 2022 10.1101/2022.09.30.510301
    [Google Scholar]
  78. Khan A. Corbett A. Ballard C. Emerging treatments for Alzheimer’s disease for non-amyloid and non-tau targets. Expert Rev. Neurother. 2017 17 7 683 695 10.1080/14737175.2017.1326818 28490260
    [Google Scholar]
  79. Snyder G.L. Vanover K.E. Zhu H. Miller D.B. O’Callaghan J.P. Tomesch J. Li P. Zhang Q. Krishnan V. Hendrick J.P. Nestler E.J. Davis R.E. Wennogle L.P. Mates S. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology 2015 232 3 605 621 10.1007/s00213‑014‑3704‑1 25120104
    [Google Scholar]
  80. Atri A. Frölich L. Ballard C. Tariot P.N. Molinuevo J.L. Boneva N. Windfeld K. Raket L.L. Cummings J.L. Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: Three randomized clinical trials. JAMA 2018 319 2 130 142 10.1001/jama.2017.20373 29318278
    [Google Scholar]
  81. Howard R Zubko O Bradley R Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: A randomized clinical trial. JAMA Neurol. 2020 77 2 164 174
    [Google Scholar]
  82. Lawlor B. Segurado R. Kennelly S. Olde Rikkert M.G.M. Howard R. Pasquier F. Börjesson-Hanson A. Tsolaki M. Lucca U. Molloy D.W. Coen R. Riepe M.W. Kálmán J. Kenny R.A. Cregg F. O’Dwyer S. Walsh C. Adams J. Banzi R. Breuilh L. Daly L. Hendrix S. Aisen P. Gaynor S. Sheikhi A. Taekema D.G. Verhey F.R. Nemni R. Nobili F. Franceschi M. Frisoni G. Zanetti O. Konsta A. Anastasios O. Nenopoulou S. Tsolaki-Tagaraki F. Pakaski M. Dereeper O. de la Sayette V. Sénéchal O. Lavenu I. Devendeville A. Calais G. Crawford F. Mullan M. NILVAD Study Group Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. PLoS Med. 2018 15 9 e1002660 10.1371/journal.pmed.1002660 30248105
    [Google Scholar]
  83. Kehoe P.G. Blair P.S. Howden B. Thomas D.L. Malone I.B. Horwood J. The rationale and design of the reducing pathology in alzheimer's disease through angiotensin targeting (RADAR) trial. J Alzheimers Dis 2018 61 2 803 814
    [Google Scholar]
  84. Song Y. Chen X. Wang L.Y. Gao W. Zhu M.J. Mei-Jia Zhu C. Rho kinase inhibitor fasudil protects against β-amyloid-induced hippocampal neurodegeneration in rats. CNS Neurosci. Ther. 2013 19 8 603 610 10.1111/cns.12116 23638992
    [Google Scholar]
  85. Killick R Ribe E Al-Shawi R Malik B Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Mol. Psychiatry 2014 19 1 88 98
    [Google Scholar]
  86. Elliott C Rojo A Ribe E Broadstock M A role for APP in Wnt signalling links synapse loss with β-amyloid production. Transl. Psychiatry 2018 8 1 179 179
    [Google Scholar]
  87. Santana S. Recuero M. Bullido M. Herpes simplex virus type I induces the accumulation of intracellular β-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells. Neurobiol. Aging 2012 33 2 430.e19 433 10.1016/j.neurobiolaging.2010.12.010
    [Google Scholar]
  88. Lerchundi R. Neira R. Valdivia S. Tau cleavage at D421 by caspase-3 is induced in neurons and astrocytes infected with herpes simplex virus type 1. J Alzheimers Dis 2011 23 3 513 520 10.3233/JAD‑2010‑101386
    [Google Scholar]
  89. Si Z Stem cell therapies in Alzheimer's disease: Applications for disease modeling. J. Pharmacol. Exp. Ther. 2021 377 2 207 217
    [Google Scholar]
  90. Sharma K. Cholinesterase inhibitors as Alzheimer’s therapeutics (Review). Mol. Med. Rep. 2019 20 2 1479 1487 31257471
    [Google Scholar]
  91. Lipton S. Calcium, free radicals and excitotoxins in neuronal apoptosis. Cell Calcium 1998 Feb-Mar 23 2-3 165 171 10.1016/s0143‑4160(98)90115‑4
    [Google Scholar]
  92. Wiese L.K. Lingler J. Lindauer A. Alzheimer’s disease and Lewy body dementia: Discerning the differences: Assessment is key for optimal management. Am. Nurse J. 2021 16 1 10 17 35815334
    [Google Scholar]
  93. Levine M.J. Empagliflozin for type 2 diabetes mellitus: An overview of phase 3 clinical trials. Curr. Diabetes Rev. 2017 13 4 405 423 27296042
    [Google Scholar]
  94. Guan L. Yang H. Cai Y. Sun L. Di P. Li W. Liu G. Tang Y. ADMET-score – A comprehensive scoring function for evaluation of chemical drug-likeness. MedChemComm 2019 10 1 148 157 10.1039/C8MD00472B 30774861
    [Google Scholar]
  95. Kalita J Chetia D Chemistry MRM Design, synthesis, antimalarial activity and docking study of 7-Chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines. Med. Chem. 2020 16 7 928 937
    [Google Scholar]
  96. Carracedo-Reboredo P. Liñares-Blanco J. Rodríguez-Fernández N. Cedrón F. Novoa F.J. Carballal A. Maojo V. Pazos A. Fernandez-Lozano C. A review on machine learning approaches and trends in drug discovery. Comput. Struct. Biotechnol. J. 2021 19 4538 4558 10.1016/j.csbj.2021.08.011 34471498
    [Google Scholar]
  97. Dighe S.N. Tippana M. van Akker S. Collet T.A. Structure-based scaffold repurposing toward the discovery of novel cholinesterase inhibitors. ACS Omega 2020 5 48 30971 30979 10.1021/acsomega.0c03848 33324805
    [Google Scholar]
  98. Dara S. Dhamercherla S. Jadav S.S. Babu C.H.M. Ahsan M.J. Machine learning in drug discovery: A review. Artif. Intell. Rev. 2022 55 3 1947 1999 10.1007/s10462‑021‑10058‑4 34393317
    [Google Scholar]
  99. Olaru A.M. Vasilache V. Danac R. Mangalagiu I.I. Antimycobacterial activity of nitrogen heterocycles derivatives: 7-(pyridine-4-yl)-indolizine derivatives. Part VII 8–12. J. Enzyme Inhib. Med. Chem. 2017 32 1 1291 1298 10.1080/14756366.2017.1375483 29072097
    [Google Scholar]
  100. Venugopala K.N. Al-Shar’i N.A. Dahabiyeh L.A. Hourani W. Deb P.K. Pillay M. Abu-Irmaileh B. Bustanji Y. Chandrashekharappa S. Tratrat C. Attimarad M. Nair A.B. Sreeharsha N. Shinu P. Haroun M. Kandeel M. Balgoname A.A. Venugopala R. Morsy M.A. Antitubercular, cytotoxicity, and computational target validation of dihydroquinazolinone derivatives. Antibiotics 2022 11 7 831 10.3390/antibiotics11070831 35884084
    [Google Scholar]
  101. Sharifi-Rad J. Rapposelli S. Sestito S. Herrera-Bravo J. Arancibia-Diaz A. Salazar L.A. Yeskaliyeva B. Beyatli A. Leyva-Gómez G. González-Contreras C. Gürer E.S. Martorell M. Calina D. Multi-target mechanisms of phytochemicals in Alzheimer’s disease: Effects on oxidative stress, neuroinflammation and protein aggregation. J. Pers. Med. 2022 12 9 1515 10.3390/jpm12091515 36143299
    [Google Scholar]
  102. dos Santos Guilherme M. Stoye N.M. Rose-John S. Garbers C. Fellgiebel A. Endres K. The synthetic retinoid acitretin increases IL-6 in the central nervous system of Alzheimer disease model mice and human patients. Front. Aging Neurosci. 2019 11 JUL 182 10.3389/fnagi.2019.00182 31396076
    [Google Scholar]
  103. Kumar N. Gahlawat A. Kumar R.N. Singh Y.P. Modi G. Garg P. Drug repurposing for Alzheimer’s disease: in silico and in vitro investigation of FDA-approved drugs as acetylcholinesterase inhibitors. J. Biomol. Struct. Dyn. 2022 40 7 2878 2892 10.1080/07391102.2020.1844054 33170091
    [Google Scholar]
  104. Iqbal U.H. Zeng E. Pasinetti G.M. The use of antimicrobial and antiviral drugs in Alzheimer’s disease. Int. J. Mol. Sci. 2020 21 14 4920 10.3390/ijms21144920 32664669
    [Google Scholar]
  105. Gong C.X. Dai C.L. Liu F. Iqbal K. Multi-targets: An unconventional drug development strategy for Alzheimer’s disease. Front. Aging Neurosci. 2022 14 837649 10.3389/fnagi.2022.837649 35222001
    [Google Scholar]
  106. Slanzi A. Iannoto G. Rossi B. Zenaro E. Constantin G. In vitro models of neurodegenerative diseases. Front. Cell Dev. Biol. 2020 8 328 10.3389/fcell.2020.00328 32528949
    [Google Scholar]
  107. Blaikie L. Kay G. Maciel P. Kong Thoo Lin P. Experimental modelling of Alzheimer’s disease for therapeutic screening. Eur. J. Med. Chem. Rep. 2022 5 100044 10.1016/j.ejmcr.2022.100044
    [Google Scholar]
  108. Salloway S.P. Sevingy J. Budur K. Pederson J.T. DeMattos R.B. Von Rosenstiel P. Paez A. Evans R. Weber C.J. Hendrix J.A. Worley S. Bain L.J. Carrillo M.C. Advancing combination therapy for Alzheimer’s disease. Alzheimers Dement. 2020 6 1 e12073 10.1002/trc2.12073 33043108
    [Google Scholar]
  109. Oprea T.I. Mestres J. Drug repurposing: Far beyond new targets for old drugs. AAPS J. 2012 14 4 759 763 10.1208/s12248‑012‑9390‑1 22826034
    [Google Scholar]
  110. Tyson R.J. Park C.C. Powell J.R. Patterson J.H. Weiner D. Watkins P.B. Gonzalez D. Precision dosing priority criteria: Drug, disease, and patient population variables. Front. Pharmacol. 2020 11 420 10.3389/fphar.2020.00420 32390828
    [Google Scholar]
  111. Tsolaki M. Fountoulakis C. Pavlopoulos I. Chatzi E. Kazis A. Prevalence and incidence of Alzheimers disease and other dementing disorders in Pylea, Greece. Am. J. Alzheimers Dis. Other Demen. 1999 14 3 138 148
    [Google Scholar]
  112. Andrieu S. Coley N. Lovestone S. Aisen P.S. Vellas B. Prevention of sporadic Alzheimer’s disease: Lessons learned from clinical trials and future directions. Lancet Neurol. 2015 14 9 926 944 10.1016/S1474‑4422(15)00153‑2 26213339
    [Google Scholar]
  113. Qiu C. Kivipelto M. von Strauss E. Epidemiology of Alzheimer’s disease: Occurrence, determinants, and strategies toward intervention. Dialogues Clin. Neurosci. 2009 11 2 111 128 10.31887/DCNS.2009.11.2/cqiu 19585947
    [Google Scholar]
  114. Tzourio C. Hypertension, cognitive decline, and dementia: An epidemiological perspective. Dialogues Clin. Neurosci. 2007 9 1 61 70 10.31887/DCNS.2007.9.1/ctzourio 17506226
    [Google Scholar]
  115. Li N Lee A Whitmer R Kivipelto M Bmj EL Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 2010 340 b5465
    [Google Scholar]
  116. Weber F.J. Latshang T.D. Blum M.R. Kohler M. Wertli M.M. Prognostic factors, disease course, and treatment efficacy in Duchenne muscular dystrophy: A systematic review and meta-analysis. Muscle Nerve 2022 66 4 462 470 10.1002/mus.27682 35860996
    [Google Scholar]
  117. Barr P Owen C Robak T Up to 8-year follow-up from RESONATE-2: First-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022 6 11 3440 3450
    [Google Scholar]
  118. Abraham H.M.A. White C.M. White W.B. The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases. Drug Saf. 2015 38 1 33 54 10.1007/s40264‑014‑0239‑7 25416320
    [Google Scholar]
  119. Guideline for the pharmacological treatment of hypertension in adults. World Health Organization Geneva 2021
    [Google Scholar]
  120. Oumata N. Lu K. Teng Y. Cavé C. Molecular mechanisms in Alzheimer’s disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules. Elsevier 2022
    [Google Scholar]
  121. Komura T Aoki M Kotoura S Protective effect of Lactococcus laudensis and Pediococcus parvulus against neuropathy due to amyloid-beta in Caenorhabditis elegans Elsevier 2022
    [Google Scholar]
  122. Zhao W. Wang J. Ho L. Identification of antihypertensive drugs which inhibit amyloid-beta protein oligomerization. J. Alzheimers Dis. 2009 16 1 49 57 10.3233/JAD‑2009‑0925
    [Google Scholar]
  123. Anekonda T. Quinn J. Harris C. L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease. Neurobiol. Dis. 2011 Jan 41 1 62 70 10.1016/j.nbd.2010.08.020
    [Google Scholar]
  124. Paris D. Bachmeier C. Patel N. Quadros A. Volmar C.H. Laporte V. Ganey J. Beaulieu-Abdelahad D. Ait-Ghezala G. Crawford F. Mullan M.J. Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier. Mol. Med. 2011 17 3-4 149 162 10.2119/molmed.2010.00180 21170472
    [Google Scholar]
  125. Moloney A. Griffin R. Timmons S. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling Elsevier 2010
    [Google Scholar]
  126. Schrijvers E Witteman J Neurology ES Insulin metabolism and the risk of Alzheimer disease: The rotterdam study. Neurology 2010 75 22 1982 1987
    [Google Scholar]
  127. Moloney A.M. Griffin R.J. Timmons S. O’Connor R. Ravid R. O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging 2010 31 2 224 243 10.1016/j.neurobiolaging.2008.04.002 18479783
    [Google Scholar]
  128. Hamilton A. Patterson S. Porter D. Gault V.A. Holscher C. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J. Neurosci. Res. 2011 89 4 481 489 10.1002/jnr.22565 21312223
    [Google Scholar]
  129. McClean P. Parthasarathy V. A novel GLP-1 analogue, prevents the impairment of learning and LTP and plaque formation in an APP/PS-1. 2011 Available from: pure.ulster.ac.uk
  130. Garber A. Handelsman Y. Grunberger G. Practice D.E.E. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary. Endocr. Pract. 2020 26 1 107 139 10.4158/CS‑2019‑0472
    [Google Scholar]
  131. Garber A. Abrahamson M. Barzilay J. Practice L.B.E. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary. Endocr. Pract. 2019 25 1 69 100 10.4158/CS‑2018‑0535
    [Google Scholar]
  132. Garber A.J. Abrahamson M.J. Barzilay J.I. Blonde L. Bloomgarden Z.T. Bush M.A. Dagogo-Jack S. DeFronzo R.A. Einhorn D. Fonseca V.A. Garber J.R. Garvey W.T. Grunberger G. Handelsman Y. Hirsch I.B. Jellinger P.S. McGill J.B. Mechanick J.I. Rosenblit P.D. Umpierrez G.E. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2018 executive summary. Endocr. Pract. 2018 24 1 91 121 10.4158/CS‑2017‑0153 29368965
    [Google Scholar]
  133. Ding Y. Qiao A. Wang Z. Goodwin J.S. Lee E.S. Block M.L. Allsbrook M. McDonald M.P. Fan G.H. Retinoic acid attenuates β-amyloid deposition and rescues memory deficits in an Alzheimer’s disease transgenic mouse model. J. Neurosci. 2008 28 45 11622 11634 10.1523/JNEUROSCI.3153‑08.2008 18987198
    [Google Scholar]
  134. Tippmann F. Hundt J. Schneider A. Endres K. Fahrenholz F. Up-regulation of the α-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 2009 23 6 1643 1654 10.1096/fj.08‑121392 19144697
    [Google Scholar]
  135. Jarvis C.I. Goncalves M.B. Clarke E. Dogruel M. Kalindjian S.B. Thomas S.A. Maden M. Corcoran J.P.T. Retinoic acid receptor-α signalling antagonizes both intracellular and extracellular amyloid-β production and prevents neuronal cell death caused by amyloid-β. Eur. J. Neurosci. 2010 32 8 1246 1255 10.1111/j.1460‑9568.2010.07426.x 20950278
    [Google Scholar]
  136. Qiao A. Li J. Hu Y. Wang J. Reports Z.Z.I.N. Reduction BACE1 expression via suppressing NF-κB mediated signaling by Tamibarotene in a mouse model of Alzheimer's disease. IBRO Neurosci. Rep. 2021 10 153 160 10.1016/j.ibneur.2021.02.004
    [Google Scholar]
  137. Cramer P.E. Cirrito J.R. Wesson D.W. Lee C.Y.D. Karlo J.C. Zinn A.E. Casali B.T. Restivo J.L. Goebel W.D. James M.J. Brunden K.R. Wilson D.A. Landreth G.E. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 2012 335 6075 1503 1506 10.1126/science.1217697 22323736
    [Google Scholar]
  138. DeMattos R. Patterson B. Fagan A. Morris J. Human apoE isoforms differentially regulate brain amyloid-b peptide clearance. Sci Transl Med. 2011 89ra57 3 89
    [Google Scholar]
  139. So P. Yip P. Bunting S. Wong L. Interactions between retinoic acid, nerve growth factor and sonic hedgehog signalling pathways in neurite outgrowth. Dev Biol. 2006 298 1 167 175 10.1016/j.ydbio.2006.06.027
    [Google Scholar]
  140. Liu C.C. Murray M.E. Li X. Zhao N. Wang N. Heckman M.G. Shue F. Martens Y. Li Y. Raulin A.C. Rosenberg C.L. Doss S.V. Zhao J. Wren M.C. Jia L. Ren Y. Ikezu T.C. Lu W. Fu Y. Caulfield T. Trottier Z.A. Knight J. Chen Y. Linares C. Wang X. Kurti A. Asmann Y.W. Wszolek Z.K. Smith G.E. Vemuri P. Kantarci K. Knopman D.S. Lowe V.J. Jack C.R. Jr Parisi J.E. Ferman T.J. Boeve B.F. Graff-Radford N.R. Petersen R.C. Younkin S.G. Fryer J.D. Wang H. Han X. Frieden C. Dickson D.W. Ross O.A. Bu G. APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Sci. Transl. Med. 2021 13 613 eabc9375 10.1126/scitranslmed.abc9375 34586832
    [Google Scholar]
  141. Kong F. Wu T. Dai J. Zhai Z. Cai J. Zhu Z. Xu Y. Sun T. Glucagon-like peptide 1 (GLP-1) receptor agonists in experimental Alzheimer’s disease models: A systematic review and meta-analysis of preclinical studies. Front. Pharmacol. 2023 14 1205207 10.3389/fphar.2023.1205207 37771725
    [Google Scholar]
  142. Wright J. Brain renin-angiotensin--a new look at an old system. Prog. Neurobiol. 2011 95 1 49 67
    [Google Scholar]
  143. Wang J Ho L Chen L Zhao Z Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J. Clin. Invest. 2007 117 11 3393 3402
    [Google Scholar]
  144. Ferrington L. Miners J. Angiotensin II-inhibiting drugs have no effect on intraneuronal Aβ or oligomeric Aβ levels in a triple transgenic mouse model of Alzheimer's disease. Am. J. Transl. Res. 2011 3 2 197 208
    [Google Scholar]
  145. Hemming M. Selkoe D. Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease. Neurobiol. Dis. 2007 Apr 26 1 273 281
    [Google Scholar]
  146. Asher S. Priefer R. Alzheimer’s disease failed clinical trials. Life Sci. 2022 306 120861 10.1016/j.lfs.2022.120861 35932841
    [Google Scholar]
  147. Deng Z. Jiang J. Wang J. Pan D. Zhu Y. Li H. Zhang X. Liu X. Xu Y. Li Y. Tang Y. Alzheimer’s Disease Neuroimaging Initiative† Angiotensin receptor blockers are associated with a lower risk of progression from mild cognitive impairment to dementia. Hypertension 2022 79 10 2159 2169 10.1161/HYPERTENSIONAHA.122.19378 35766029
    [Google Scholar]
  148. Bild W. Vasincu A. Rusu R.N. Ababei D.C. Stana A.B. Stanciu G.D. Savu B. Bild V. Impact of the renin-angiotensin system on the pathogeny and pharmacotherapeutics of neurodegenerative diseases. Biomolecules 2022 12 10 1429 10.3390/biom12101429 36291638
    [Google Scholar]
  149. Kivipelto M. Palmer K. Hoang T.D. Yaffe K. Trials and treatments for vascular brain health: Risk factor modification and cognitive outcomes. Stroke 2022 53 2 444 456 10.1161/STROKEAHA.121.032614 35000424
    [Google Scholar]
  150. Gouveia F. Camins A. Ettcheto M. Bicker J. Falcão A. Cruz M.T. Fortuna A. Targeting brain renin-angiotensin system for the prevention and treatment of Alzheimer’s disease: Past, present and future. Ageing Res. Rev. 2022 77 101612 10.1016/j.arr.2022.101612 35346852
    [Google Scholar]
  151. Ganz T. Fainstein N. Ben-Hur T. When the infectious environment meets the AD brain. Mol. Neurodegener. 2022 17 1 53 10.1186/s13024‑022‑00559‑3 35986296
    [Google Scholar]
  152. Danielyan L. Klein R. Hanson L.R. Buadze M. Schwab M. Gleiter C.H. Frey W.H. II Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuvenation Res. 2010 13 2-3 195 201 10.1089/rej.2009.0944 20370487
    [Google Scholar]
  153. Iwasaki K. Egashira N. Nilvadipine prevents the impairment of spatial memory induced by cerebral ischemia combined with beta-amyloid in rats. Biol. Pharm. Bull. 2007 30 4 698 701 10.1248/bpb.30.698
    [Google Scholar]
  154. Martin D.M. McClintock S.M. Forster J.J. Lo T.Y. Loo C.K. Cognitive enhancing effects of rTMS administered to the prefrontal cortex in patients with depression: A systematic review and meta-analysis of individual task effects. Depress. Anxiety 2017 34 11 1029 1039 10.1002/da.22658 28543994
    [Google Scholar]
  155. Copenhaver P. A translational continuum of model systems for evaluating treatment strategies in Alzheimer's disease: Isradipine as a candidate drug. Dis. Model. Mech. 2011 4 5 634 648 10.1242/dmm.006841
    [Google Scholar]
  156. López-Arrieta J.M. Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst. Rev. 2002 3 CD000147 12137606
    [Google Scholar]
  157. Kennelly S. Abdullah L. Kenny R.A. Mathura V. Luis C.A. Mouzon B. Crawford F. Mullan M. Lawlor B. Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer’s patients—an open-label trial. Int. J. Geriatr. Psychiatry 2012 27 4 415 422 10.1002/gps.2735 21560164
    [Google Scholar]
  158. Qin M. Wu J. Zhou Q. Liang Z. Su Y. Global cognitive effects of second-generation antidepressants in patients with Alzheimer’s disease: A systematic review and meta-analysis of randomized controlled trials. J. Psychiatr. Res. 2022 155 371 379 10.1016/j.jpsychires.2022.09.039 36182766
    [Google Scholar]
  159. Khachaturian A Zandi P Antihypertensive medication use and incident Alzheimer disease: The cache county study. Arch. Neurol. 2006 63 5 686 692 10.1001/archneur.63.5.noc60013
    [Google Scholar]
  160. Hampel H. Vergallo A. Aguilar L.F. Benda N. Broich K. Cuello A.C. Cummings J. Dubois B. Federoff H.J. Fiandaca M. Genthon R. Haberkamp M. Karran E. Mapstone M. Perry G. Schneider L.S. Welikovitch L.A. Woodcock J. Baldacci F. Lista S. Alzheimer Precision Medicine Initiative (APMI) Precision pharmacology for Alzheimer’s disease. Pharmacol. Res. 2018 130 331 365 10.1016/j.phrs.2018.02.014 29458203
    [Google Scholar]
  161. Sim S. Wong N. Nanotechnology and its use in imaging and drug delivery (Review). Biomed. Rep. 2021 14 5 42 10.3892/br.2021.1418 33728048
    [Google Scholar]
  162. Li L. He R. Yan H. Leng Z. Zhu S. Gu Z. Nanotechnology for the diagnosis and treatment of Alzheimer’s disease: A bibliometric analysis. Nano Today 2022 47 101654 10.1016/j.nantod.2022.101654
    [Google Scholar]
  163. Stewart S.A. Domínguez-Robles J. Donnelly R.F. Larrañeta E. Implantable polymeric drug delivery devices: Classification, manufacture, materials, and clinical applications. Polymers 2018 10 12 1379 10.3390/polym10121379 30961303
    [Google Scholar]
  164. Stewart S. Domínguez-Robles J. McIlorum V. Mancuso E. Lamprou D. Donnelly R. Larrañeta E. Development of a biodegradable subcutaneous implant for prolonged drug delivery using 3D printing. Pharmaceutics 2020 12 2 105 10.3390/pharmaceutics12020105 32013052
    [Google Scholar]
  165. Jamróz W. Szafraniec J. Kurek M. Jachowicz R. 3D printing in pharmaceutical and medical applications – Recent achievements and challenges. Pharm. Res. 2018 35 9 176 10.1007/s11095‑018‑2454‑x 29998405
    [Google Scholar]
  166. Vaz V.M. Kumar L. 3D printing as a promising tool in personalized medicine. AAPS PharmSciTech 2021 22 1 49 10.1208/s12249‑020‑01905‑8 33458797
    [Google Scholar]
  167. Liang Y. Duan L. Lu J. Xia J. Engineering exosomes for targeted drug delivery. Theranostics 2021 11 7 3183 3195 10.7150/thno.52570 33537081
    [Google Scholar]
  168. Ortega A. Martinez-Arroyo O. Forner M.J. Cortes R. Exosomes as drug delivery systems: Endogenous nanovehicles for treatment of systemic lupus erythematosus. Pharmaceutics 2020 13 1 3 10.3390/pharmaceutics13010003 33374908
    [Google Scholar]
  169. Abou M.B. Sun L. Wei H. Approaches to optimizing dantrolene neuroprotection for the treatment of Alzheimer’s disease. Curr. Alzheimer Res. 2020 17 4 324 328 10.2174/1567205017666200522204722 32442084
    [Google Scholar]
  170. Lavanya Jakki S. Senthil V. Chandrasekar M. The blood brain barrier and its role in Alzheimer’s therapy: An overview. Curr. Drug Targets 2017 18
    [Google Scholar]
  171. Zhu S. Bai Q. Li L. Xu T. Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents. Comput. Struct. Biotechnol. J. 2022 20 2839 2847 10.1016/j.csbj.2022.05.057 35765655
    [Google Scholar]
  172. Cunha S. Forbes B. Sousa Lobo J.M. Silva A.C. Improving drug delivery for alzheimer’s disease through nose-to-brain delivery using nanoemulsions, nanostructured lipid carriers (NLC) and in situ hydrogels. Int. J. Nanomedicine 2021 16 4373 4390 10.2147/IJN.S305851 34234432
    [Google Scholar]
  173. Paul D. Sanap G. Shenoy S. Kalyane D. Kalia K. Tekade R.K. Artificial intelligence in drug discovery and development. Drug Discov. Today 2021 26 1 80 93 10.1016/j.drudis.2020.10.010 33099022
    [Google Scholar]
  174. Prashansa A. Artificial intelligence in drug discovery and development. J. Pharm. Vigil. 2018 06 2 1000e173 10.4172/2329‑6887.1000e173
    [Google Scholar]
  175. Warren J.B. Translating the dose response into risk and benefit. Br. J. Clin. Pharmacol. 2019 85 10 2187 2193 10.1111/bcp.13949 30945324
    [Google Scholar]
  176. McGhee D.J.M. Ritchie C.W. Zajicek J.P. Counsell C.E. A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer’s disease and Parkinson’s disease. BMC Neurol. 2016 16 1 92 10.1186/s12883‑016‑0606‑3 27312378
    [Google Scholar]
  177. Arnold S.E. Betensky R.A. Multicrossover randomized controlled trial designs in Alzheimer disease. Ann. Neurol. 2018 84 2 168 175 10.1002/ana.25280 30014506
    [Google Scholar]
  178. Ottenhoff L. Vijverberg E.G.B. Visser L.N.C. Verijp M. Prins N.D. Van der Flier W.M. Sikkes S.A.M. Experiences of and recommendations on clinical trial design in Alzheimer’s disease from the participant’s point of view: A mixed-methods study in two clinical trial centers in the Netherlands. Alzheimers Res. Ther. 2023 15 1 72 10.1186/s13195‑023‑01190‑0 37016435
    [Google Scholar]
  179. Randomized controlled trials: Overview, benefits, and limitations. Available from: https://www.medicalnewstoday.com/articles/280574
  180. White H. Sabarwal S. de Hoop T. Randomized controlled trials (RCTs). Methodological Briefs. Impact Evaluation. 2014 Sep 7
    [Google Scholar]
  181. Thall P.F. Adaptive enrichment designs in clinical trials. Annu. Rev. Stat. Appl. 2021 8 1 393 411 10.1146/annurev‑statistics‑040720‑032818 36212769
    [Google Scholar]
  182. Cummings J. The role of biomarkers in Alzheimer's disease drug development. Adv. Exp. Med. Biol. 2019 1118 29 61 10.1007/978‑3‑030‑05542‑4_2
    [Google Scholar]
  183. Carey A. Fossati S. Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer’s disease and dementia: New evidence, potential therapeutic strategies, and biomarkers. Alzheimers Dement. 2023 19 2 671 695 10.1002/alz.12871 36401868
    [Google Scholar]
  184. Sica D.A. Weber M. The losartan intervention for endpoint reduction (LIFE) trial-have angiotensin-receptor blockers come of age? J. Clin. Hypertens. 2002 4 4 301 305 10.1111/j.1524‑6175.2002.01099.x 12147937
    [Google Scholar]
  185. Hariton E. Locascio J.J. Randomised controlled trials – The gold standard for effectiveness research. BJOG 2018 125 13 1716 10.1111/1471‑0528.15199 29916205
    [Google Scholar]
  186. Simon N. Simon R. Adaptive enrichment designs for clinical trials. Biostatistics 2013 14 4 613 625 10.1093/biostatistics/kxt010 23525452
    [Google Scholar]
  187. Cummings J. Apostolova L. Rabinovici G.D. Atri A. Aisen P. Greenberg S. Hendrix S. Selkoe D. Weiner M. Petersen R.C. Salloway S. Lecanemab: Appropriate use recommendations. J. Prev. Alzheimers Dis. 2023 10 3 362 377 37357276
    [Google Scholar]
  188. Barcikowska M. Guideline on the clinical investigation of medicines for the treatment of Alzheimer’s disease. Lekarz POZ. 2018 4 5 370 374
    [Google Scholar]
  189. Akram M. Nawaz A. Effects of medicinal plants on Alzheimer’s disease and memory deficits. Neural Regen. Res. 2017 12 4 660 670 10.4103/1673‑5374.205108 28553349
    [Google Scholar]
  190. Guidance for industry and investigators safety reporting requirements for INDs and BA/BE Studies US Food and Drug Administration 2012
    [Google Scholar]
  191. Guideline on good pharmacovigilance practices (GVP) - Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products. 2017 Available from: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-good-pharmacovigilance-practices-gvp-module-vi-collection-management-and-submission-reports-suspected-adverse-reactions-medicinal-products-rev-2_en.pdf
  192. Singh R.K. Recent trends in the management of Alzheimer’s disease: Current therapeutic options and drug repurposing approaches. Curr. Neuropharmacol. 2020 18 9 868 882 10.2174/1570159X18666200128121920 31989900
    [Google Scholar]
  193. Niu J. Straubinger R.M. Mager D.E. Pharmacodynamic drug–drug interactions. Clin. Pharmacol. Ther. 2019 105 6 1395 1406 10.1002/cpt.1434 30912119
    [Google Scholar]
  194. Maqbool M. Dar M.A. Rasool S. Bhat A.U. Geer M.I. Drug safety and Pharmacovigilance: An overview. J. Drug Deliv. Ther. 2019 9 2-s 543 548 10.22270/jddt.v9i2‑s.2469
    [Google Scholar]
  195. Lavan A.H. Gallagher P. Predicting risk of adverse drug reactions in older adults. Ther. Adv. Drug Saf. 2016 7 1 11 22 10.1177/2042098615615472 26834959
    [Google Scholar]
  196. Ivulich S. Snell G. Long-term management of elderly patients taking immunosuppressive medications. Aust. J. Gen. Pract. 2020 49 3 100 106 10.31128/AJGP‑10‑19‑5137 32113211
    [Google Scholar]
  197. Howard R. Zubko O. Bradley R. Harper E. Pank L. O’Brien J. Fox C. Tabet N. Livingston G. Bentham P. McShane R. Burns A. Ritchie C. Reeves S. Lovestone S. Ballard C. Noble W. Nilforooshan R. Wilcock G. Gray R. Minocycline in Alzheimer Disease Efficacy (MADE) Trialist Group Minocycline at 2 different dosages vs placebo for patients with mild alzheimer disease. JAMA Neurol. 2020 77 2 164 174 10.1001/jamaneurol.2019.3762 31738372
    [Google Scholar]
  198. Cummings J. Morstorf T. Lee G. Alzheimer’s drug-development pipeline: 2016. Alzheimers Dement. 2016 2 4 222 232 10.1016/j.trci.2016.07.001 29067309
    [Google Scholar]
  199. Monge A.N. Sigelman D.W. Temple R.J. Chahal H.S. Use of US Food and Drug Administration expedited drug development and review programs by orphan and nonorphan novel drugs approved from 2008 to 2021. JAMA Network Open. 2022 5 11 e2239336 30041014
    [Google Scholar]
  200. Salminen WF Wiles ME Stevens RE Kesselheim AS Streamlining nonclinical drug development using the FDA 505(b)(2) new drug application regulatory pathway. Drug Discov. Today 2019 24 1 46 56 30041014
    [Google Scholar]
  201. Hwang TJ Ross JS Vokinger KN Kesselheim AS Association between FDA and EMA expedited approval programs and therapeutic value of new medicines: Retrospective cohort study. BMJ 2020 371
    [Google Scholar]
  202. Hanaizi Z. Kweder S. Thor S. Ribeiro S. Marcal A. Considering global development? Insights from applications for fda breakthrough therapy and EMA PRIME designations. Ther. Innov. Regul. Sci. 2023 57 2 321 328 10.1007/s43441‑022‑00475‑0 36307671
    [Google Scholar]
  203. Cummings J. Lee G. Nahed P. Kambar M.E.Z.N. Zhong K. Fonseca J. Taghva K. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement. 2022 8 1 e12295 10.1002/trc2.12295 35516416
    [Google Scholar]
  204. Nauck M.A. Quast D.R. Wefers J. Meier J.J. GLP-1 receptor agonists in the treatment of type 2 diabetes – State-of-the-art. Mol. Metab. 2021 46 101102 10.1016/j.molmet.2020.101102 33068776
    [Google Scholar]
  205. Hsieh K.L. Plascencia-Villa G. Lin K.H. Perry G. Jiang X. Kim Y. Synthesize heterogeneous biological knowledge via representation learning for Alzheimer’s disease drug repurposing. iScience 2023 26 1 105678 10.1016/j.isci.2022.105678 36594024
    [Google Scholar]
  206. Shah S. Famta P. Fernandes V. Bagasariya D. Charankumar K. Kumar Khatri D. Bala Singh S. Srivastava S. Quality by design steered development of Niclosamide loaded liposomal thermogel for Melanoma: In vitro and Ex vivo evaluation. Eur. J. Pharm. Biopharm. 2022 180 119 136 10.1016/j.ejpb.2022.09.024 36198344
    [Google Scholar]
  207. Wu Q. Su S. Cai C. Xu L. Fan X. Ke H. Dai Z. Fang S. Zhuo Y. Wang Q. Pan H. Gu Y. Fang J. Network Proximity-based computational pipeline identifies drug candidates for different pathological stages of Alzheimer’s disease. Comput. Struct. Biotechnol. J. 2023 21 1907 1920 10.1016/j.csbj.2023.02.041 36936813
    [Google Scholar]
  208. Madugula S.S. John L. Nagamani S. Gaur A.S. Poroikov V.V. Sastry G.N. Molecular descriptor analysis of approved drugs using unsupervised learning for drug repurposing. Comput. Biol. Med. 2021 138 104856 10.1016/j.compbiomed.2021.104856 34555571
    [Google Scholar]
  209. Grabowska M.E. Huang A. Wen Z. Li B. Wei W.Q. Drug repurposing for Alzheimer’s disease from 2012–2022—a 10-year literature review. Front. Pharmacol. 2023 14 1257700 10.3389/fphar.2023.1257700 37745051
    [Google Scholar]
  210. Femminella G.D. Frangou E. Love S.B. Busza G. Holmes C. Ritchie C. Lawrence R. McFarlane B. Tadros G. Ridha B.H. Bannister C. Walker Z. Archer H. Coulthard E. Underwood B.R. Prasanna A. Koranteng P. Karim S. Junaid K. McGuinness B. Nilforooshan R. Macharouthu A. Donaldson A. Thacker S. Russell G. Malik N. Mate V. Knight L. Kshemendran S. Harrison J. Brooks D.J. Passmore A.P. Ballard C. Edison P. Edison P. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: Study protocol for a randomised controlled trial (ELAD study). Trials 2019 20 1 191 10.1186/s13063‑019‑3259‑x 30944040
    [Google Scholar]
  211. Prince M. Wimo A. Gurchet M. Ali G. Yu Y. Prime M. World Alzheimer Report 2015—the global impact of dementia: An analysis of prevalence, incidence, cost and trends. 2015 Available from: https://www.google.com/search?sca_esv=563294644&sxsrf=AB5stBh5CPoG8nZNHCtR-VCMOOEoBeo6SQ:1694062133183&q=Prince+M,+Wimo+A,+Gurchet+M,+Ali+G,+Yu+Y,+Prime+M.+World+Alzheimer+Report+2015—the+global+impact+of+dementia:+an+analysis+of+prevalence,+incidence,+cost+and+trends.+2015&spell=1&sa=X&ved=2ahUKEwj_ubOd2ZeBAxUxSWwGHbXjCBIQBSgAegQIChAB&biw=1536&bih=739&dpr=1.25
  212. Wimo A. Seeher K. Cataldi R. Cyhlarova E. Dielemann J.L. Frisell O. Guerchet M. Jönsson L. Malaha A.K. Nichols E. Pedroza P. Prince M. Knapp M. Dua T. The worldwide costs of dementia in 2019. Alzheimers Dement. 2023 19 7 2865 2873 10.1002/alz.12901 36617519
    [Google Scholar]
  213. Levetiracetam: The anti-convulsant of choice for elderly patients with dementia. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT01318408?id=NCT01318408&draw=2&rank=1&load=cart
  214. Vossel K. Ranasinghe K.G. Beagle A.J. La A. Ah Pook K. Castro M. Mizuiri D. Honma S.M. Venkateswaran N. Koestler M. Zhang W. Mucke L. Howell M.J. Possin K.L. Kramer J.H. Boxer A.L. Miller B.L. Nagarajan S.S. Kirsch H.E. Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity. JAMA Neurol. 2021 78 11 1345 1354 10.1001/jamaneurol.2021.3310 34570177
    [Google Scholar]
  215. Sanford-Burnham researchers develop new drug that reverses loss of brain connections in Alzheimer’s. Available from: https://www.fiercebiotech.com/research/sanford-burnham-researchers-develop-new-drug-reverses-loss-of-brain-connections-alzheimer
  216. Kabir M.T. Sufian M.A. Uddin M.S. Begum M.M. Akhter S. Islam A. Mathew B. Islam M.S. Amran M.S. Md Ashraf G. NMDA receptor antagonists: Repositioning of memantine as a multitargeting agent for Alzheimer’s therapy. Curr. Pharm. Des. 2019 25 33 3506 3518 10.2174/1381612825666191011102444 31604413
    [Google Scholar]
  217. Kaeberlein M. Galvan V. Rapamycin and Alzheimer’s disease: Time for a clinical trial? Sci. Transl. Med. 2019 11 476 eaar4289 10.1126/scitranslmed.aar4289 30674654
    [Google Scholar]
  218. Carosi J.M. Sargeant T.J. Rapamycin and Alzheimer disease: A double-edged sword? Autophagy 2019 15 8 1460 1462 10.1080/15548627.2019.1615823 31066320
    [Google Scholar]
  219. Ghiam M.K. Patel S.D. Hoffer A. Selman W.R. Hoffer B.J. Hoffer M.E. Drug repurposing in the treatment of traumatic brain injury. Front. Neurosci. 2021 15 635483 10.3389/fnins.2021.635483 33833663
    [Google Scholar]
  220. Wong C. Gregory J.M. Liao J. Egan K. Vesterinen H.M. Ahmad Khan A. Anwar M. Beagan C. Brown F.S. Cafferkey J. Cardinali A. Chiam J.Y. Chiang C. Collins V. Dormido J. Elliott E. Foley P. Foo Y.C. Fulton-Humble L. Gane A.B. Glasmacher S.A. Heffernan Á. Jayaprakash K. Jayasuriya N. Kaddouri A. Kiernan J. Langlands G. Leighton D. Liu J. Lyon J. Mehta A.R. Meng A. Nguyen V. Park N.H. Quigley S. Rashid Y. Salzinger A. Shiell B. Singh A. Soane T. Thompson A. Tomala O. Waldron F.M. Selvaraj B.T. Chataway J. Swingler R. Connick P. Pal S. Chandran S. Macleod M. Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus. BMJ Open 2023 13 2 e064169 10.1136/bmjopen‑2022‑064169 36725099
    [Google Scholar]
  221. Desai R.J. Varma V.R. Gerhard T. Segal J. Mahesri M. Chin K. Nonnenmacher E. Gabbeta A. Mammen A.M. Varma S. Horton D.B. Kim S.C. Schneeweiss S. Thambisetty M. Targeting abnormal metabolism in Alzheimer’s disease: The drug repurposing for effective alzheimer’s medicines (dream) study. Alzheimers Dement. 2020 6 1 e12095 10.1002/trc2.12095 33304987
    [Google Scholar]
  222. Ehrhardt S. Porsteinsson A.P. Munro C.A. Rosenberg P.B. Pollock B.G. Devanand D.P. Mintzer J. Rajji T.K. Ismail Z. Schneider L.S. Baksh S.N. Drye L.T. Avramopoulos D. Shade D.M. Lyketsos C.G. S-CitAD Research Group Escitalopram for agitation in Alzheimer’s disease (S-CitAD): Methods and design of an investigator-initiated, randomized, controlled, multicenter clinical trial. Alzheimers Dement. 2019 15 11 1427 1436 10.1016/j.jalz.2019.06.4946 31587995
    [Google Scholar]
  223. Farouk I.A. Low Z.Y. Puniyamurti A. Zabidi N.Z. Amin M.K.A. Lal S.K. Genomic approaches for drug repositioning. Biomedical Translational Research Springer Singapore 2022 49 72
    [Google Scholar]
  224. Cook M.A. Wright G.D. The past, present, and future of antibiotics. Sci. Transl. Med. 2022 14 657 eabo7793 10.1126/scitranslmed.abo7793 35947678
    [Google Scholar]
  225. Wang R. Reddy P.H. Role of glutamate and NMDA receptors in Alzheimer’s disease. J. Alzheimers Dis. 2017 57 4 1041 1048 10.3233/JAD‑160763 27662322
    [Google Scholar]
  226. Sheldon A.L. Robinson M.B. The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem. Int. 2007 51 6-7 333 355 10.1016/j.neuint.2007.03.012 17517448
    [Google Scholar]
  227. Meyer T. Münch C. Völkel H. Booms P. Ludolph A.C. The EAAT2 (GLT-1) gene in motor neuron disease: Absence of mutations in amyotrophic lateral sclerosis and a point mutation in patients with hereditary spastic paraplegia. J. Neurol. Neurosurg. Psychiatry 1998 65 4 594 596 10.1136/jnnp.65.4.594 9771796
    [Google Scholar]
  228. Jackson M. Steers G. Nigel Leigh P. Morrison K.E. Polymorphisms in the glutamate transporter gene EAAT2 in European ALS patients. J. Neurol. 1999 246 12 1140 1144 10.1007/s004150050532 10653305
    [Google Scholar]
  229. Rosenblum L.T. Trotti D. EAAT2 and the molecular signature of amyotrophic lateral sclerosis. Adv. Neurobiol. 2017 16 117 136 10.1007/978‑3‑319‑55769‑4_6 28828608
    [Google Scholar]
  230. Ambati J. Neuron B.F. Mechanisms of age-related macular degeneration. Neuron 2012 75 1 26 39 10.1016/j.neuron.2012.06.018
    [Google Scholar]
  231. Rothstein J Patel S Regan M Nature CH Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005 433 7021 73 77 10.1038/nature03180
    [Google Scholar]
  232. Obrenovich M. Jaworski H. Tadimalla T. Mistry A. Sykes L. Perry G. Bonomo R. The role of the microbiota–gut–brain axis and antibiotics in ALS and neurodegenerative diseases. Microorganisms 2020 8 5 784 10.3390/microorganisms8050784 32456229
    [Google Scholar]
  233. Clinical trial ceftriaxone in subjects With ALS - Full text view. Available from: https://clinicaltrials.gov/ct2/show/NCT00349622
  234. Cudkowicz M. Titus S. Kearney M. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: A multi-stage, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2014 13 11 1083 1091 10.1016/S1474‑4422(14)70222‑4
    [Google Scholar]
  235. McDonnell E. Schoenfeld D. Paganoni S. Atassi N. Causal inference methods to study gastric tube use in amyotrophic lateral sclerosis. Neurology 2017 89 14 1483 1489 10.1212/WNL.0000000000004534 28864675
    [Google Scholar]
  236. Yimer E.M. Hishe H.Z. Tuem K.B. Repurposing of the β-lactam antibiotic, ceftriaxone for neurological disorders: A review. Front. Neurosci. 2019 13 236 10.3389/fnins.2019.00236 30971875
    [Google Scholar]
  237. Mittal S. Bjørnevik K. Im D.S. Flierl A. Dong X. Locascio J.J. Abo K.M. Long E. Jin M. Xu B. Xiang Y.K. Rochet J.C. Engeland A. Rizzu P. Heutink P. Bartels T. Selkoe D.J. Caldarone B.J. Glicksman M.A. Khurana V. Schüle B. Park D.S. Riise T. Scherzer C.R. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease. Science 2017 357 6354 891 898 10.1126/science.aaf3934 28860381
    [Google Scholar]
  238. Stefanis L. α-Synuclein in Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2012 2 2 a009399 10.1101/cshperspect.a009399 22355802
    [Google Scholar]
  239. Ntetsika T. Papathoma P.E. Markaki I. Novel targeted therapies for Parkinson’s disease. Mol. Med. 2021 27 1 17 10.1186/s10020‑021‑00279‑2 33632120
    [Google Scholar]
  240. Itoh N. Ohta H. Roles of FGF20 in dopaminergic neurons and Parkinson’s disease. Front. Mol. Neurosci. 2013 6 MAY 15 10.3389/fnmol.2013.00015 23754977
    [Google Scholar]
  241. Liu Y. Deng J. Liu Y. Li W. Nie X. FGF, mechanism of action, role in Parkinson’s disease, and therapeutics. Front. Pharmacol. 2021 12 675725 10.3389/fphar.2021.675725 34234672
    [Google Scholar]
  242. Zheng H. Fridkin M. Youdim M. New approaches to treating Alzheimer’s disease. Perspect. Medicin. Chem. 2015 7 PMC.S13210 10.4137/PMC.S13210 25733799
    [Google Scholar]
  243. Fletcher E.J.R. Jamieson A.D. Williams G. Doherty P. Duty S. Targeted repositioning identifies drugs that increase fibroblast growth factor 20 production and protect against 6-hydroxydopamine-induced nigral cell loss in rats. Sci. Rep. 2019 9 1 8336 10.1038/s41598‑019‑44803‑1 31171821
    [Google Scholar]
  244. Park K. Risk of stroke associated with nonsteroidal anti-inflammatory drugs. Vasc. Health Risk Manag. 2014 10 25 32 10.2147/VHRM.S54159
    [Google Scholar]
  245. Neuroprotective K Natarajan K Yu J Hanson CK Neuroprotective effects and therapeutic potential of the citrus flavonoid hesperetin in neurodegenerative diseases. Nutrients 2022 14 11 2228 10.3390/nu14112228
    [Google Scholar]
  246. Markulin I. Matasin M. Turk V.E. Salković-Petrisic M. Challenges of repurposing tetracyclines for the treatment of Alzheimer’s and Parkinson’s disease. J. Neural Transm. 2022 129 5-6 773 804 10.1007/s00702‑021‑02457‑2 34982206
    [Google Scholar]
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