Drug Used in the Treatment of Alzheimer’s Disease and New Approaches

Öz

Alzheimer’s disease, which is responsible for the majority of the dementia cases, has become an important health problem especially in western countries due to the rapidly aging population. Though the nature of the disease has not been totally understood yet drug development studies continue based on various hypotheses. None of the current drugs can not stop or reverse the progress of the disease. In this review,  current drugs and new targets are included. In this context, current drugs, approaches based on amiloid and tau hypotheses, and relationship between microglial cells and Alzheimer’s disease are researched and molecul examples developed for new targets are included.

Alzheimer Hastalığının Tedavisinde Kullanılan İlaçlar ve Yeni Yaklaşımlar

Öz

Demansların büyük çoğunluğundan sorumlu olan Alzheimer Hastalığı hızla yaşlanan nüfusla birlikte özellikle batı toplumlarında büyük bir sağlık sorunu haline gelmiştir. Hastalığın doğası tam olarak anlaşılamasa da çeşitli hipotezlere dayalı olarak ilaç geliştirme çalışmaları devam etmektedir. Mevcut ilaçlardan hiçbiri hastalığın ilerleyişini durduramamakta ya da geri çevirememektedir. Bu nedenle de hastalığın temelini hedef alan yeni ilaçlara büyük bir gereksinim vardır. Bu derlemede Alzheimer Hastalığı için mevcut olarak kullanılan ilaçlara ve yeni hedeflere yer verilmiştir. Bu kapsamda mevcut ilaçlar, amiloid hipotezini temel alan yaklaşımlar, tau hipotezini temel alan yaklaşımlar ve mikroglialar ile Alzheimer Hastalığı arasındaki ilişki incelenmiş, yeni hedeflere yönelik geliştirilen molekül örneklerine yer verilmiştir

Anahtar Kelimeler

• alzheimer

Kaynakça

1. 1. Müller P, Fendt M, Müller NG 2019. “Drug treatment of Alzheimer's dementia : Status quo and perspectives” Internist (Berl).doi: 10.1007/s00108-019-0625-4.
2. 2. Hawkins K.E, Duchen M., 2019. “Modelling mitochondrial dysfunction in Alzheimer’s disease using human induced pluripotent stem cells” World J Stem Cells. 11(5): 236–253.
3. 3. Saito S., Yamamoto Y., Ihara M., 2019. “Development of a Multicomponent Intervention to Prevent Alzheimer's Disease” Front Neurol. 8;10:490.
4. 4. Nonaka S., Nakanishi H., 2019. “Microglial clearance of focal apoptotic synapses” Neurosci Lett. 5:134317.
5. 5. Lane C.A., Hardy J., Schott J.M., 2018. “Alzheimer's disease” Eur J Neurol. 25(1):59-70.
6. 6. Chen X.Q., Mobley W.C. 2019. “Exploring the Pathogenesis of Alzheimer Disease in Basal For Brain Cholinergic Neurons: Converging Insights From Alternative Hypotheses” Front Neurosci. 7;13:446.
7. 7. Márquez F., Yassa M.A., 2019. “Neuroimaging Biomarkers for Alzheimer's Disease” Mol Neurodegener. 7;14(1):21.
8. 8. Herrmann N., Chau SA., Kircanski I., Lanctôt K.L., 2011. “Current and Emerging Drug Treatment Options for Alzheimer’s Disease A Systematic Review” Drugs 71 (15): 2031-2065.

9. 9. Colović M.B., Krstić D.Z., Lazarević-Pašti T.D., Bondžić A.M., Vasić V.M., 2013. “Acetylcholinesterase inhibitors: pharmacology and toxicology” Curr Neuropharmacol. 11(3):315–335
10. 10. Radic Z., Taylor P., 2001. “Peripheral Site Ligands Accelerate Inhibition of Acetylcholinesterase by Neutral Organophosphates” J. Appl. Toxicol. 21, 13–14.
11. 11. Axelsen P.H., Harel M., Silman I., Sussman J.L., 1994. “Structure and Dynamics of the active site gorge of acetylcholineesterase: synergistic use of molecular Dynamics simulation and X-ray crystallography”Protein Sci. 3(2): 188–197
12. 12. Marum, R.J.V., 2009. “Update on the use of memantine in Alzheimer’s disease”Neuropsychiatr Dis Treat. 2009; 5: 237–247.
13. 13. Wallace T.L., Porter R.H.P., 2011. “Targeting the nicotinic alpha7 acetylcholine receptor to enhance cognitionin disease” Biochemical Pharmacology 82 891–903.
14. 14. Liu Q., Kawai H., Berg D.K., 2001.“beta-Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons”Proc Natl Acad Sci USA, 98, 4734-4739
15. 15. Hashimoto K., Koike K., Shimizu E., Iyo M., 2005. “α7 Nicotinic Receptor Agonists as Potential Therapeutic Drugs for Schizophrenia” Curr. Med. Chem. – Central Nervous System Agents. 5. 171-184.
16. 16. Lao K., Ji N., Zhang X., Qiao W., Tang Z., Gou X., 2019” Drug development for Alzheimer’s disease: review” Journal of Drug Targeting, 27:2, 164-173
17. 17. Murphy MP, LeVine H 3rd., 2010. “Alzheimer's disease and the amyloid-beta peptide”. J Alzheimers Dis. 19(1):311–323.
18. 18. Bongarzone S., Savickas V., Luzi F., Gee A.D., 2017. “Targeting the Receptor for Advanced Glycation Endproducts (RAGE): A Medicinal Chemistry Perspective”. J Med Chem. 60(17):7213–7232.
19. 19. Scott J.D., Li S.W., Brunskill A.P.J., Chen X., Cox K., Cumming J.N., Forman M., Gilbert E.J., Hodgson R.A., Hyde L.A., Jiang Q., Iserloh U., Kazakevich I., Kuvelkar R., Mei H., Meredith J., Misiaszek J., Orth P., Rossiter L.M., Slater M., Stone J., Strickland C.O., Voigt J.H., Wang G., Wang H., Wu Y., Greenlee W.J., Parker E.M., Kennedy M.E., Stamford A.W., 2016. “Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease” Journal of Medicinal Chemistry 59 (23), 10435-10450.
20. 20. Egan F.M., Kost J., Voss T., Mukai Y., Aisen P.S., Cummings J.L., Tariot P.N., Vellas B., Dyck C.H.V., Boada M., Zhang Y., Li W., Furtek C., Mahoney E., Mozley L.H., Mo Y., Sur C., Michelson D., 2019. “Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease” N Engl J Med 380:1408-20
21. 21. Olsauskas-Kuprys R, Zlobin A, Osipo C., 2013.“Gamma secretase inhibitors of Notch signaling”. Onco Targets Ther. 6:943–955.
22. 22. Strooper B.D., 2014. “ Lessons from a Failed γ-Secretase Alzheimer Trial”Cell. 159(4), 721-726
23. 23. Wolfe M.S., 2008. “Inhibition and modulation of γ-secretase for Alzheimer’s disease” Neurotherapeutics 5(3): 391–398
24. 24. Weggen S., Rogers M., Eriksen J., 2007. “NSAIDs: small molecules for prevention of Alzheimer’s disease orprecursors for future drug development?” TRENDS in Pharmacological Sciences 28(10), 536-543
25. 25. Imbimbo B.P., 2009. “Why did tarenflurbil fail in Alzheimer's disease?” J Alzheimers Dis. 17(4):757-60
26. 26. Kierdorf K., Fritz G., 2013. “RAGE regulation and signaling in inflammation and beyond”J Leukoc Biol. 94(1):55-68
27. 27. Han Y.T., Choi G.I., Son D., Kim N.J., Yun H., Lee S., Chang D.J., Hong H.S., Kim H., Ha H.J., Kim Y.H., Park H.J., Lee J., Suh Y.G., 2012.” Ligand-Based Design, Synthesis, and Biological Evaluation of 2- Aminopyrimidines, a Novel Series of Receptor for Advanced Glycation End Products (RAGE) Inhibitors “J. Med. Chem., 55 (21), 9120–9135
28. 28. Bendlin B.B., 2019. “Antidiabetic therapies and Alzheimer disease” DIALOGUESIN CLINICAL NEUROSCIENCE 21(1); 83-91
29. 29. Grundke-Iqbal I., Iqbal K.,Tung Y.C.,Quinlan M., Wisniewski H.M.,Binder L.I., 1986. “Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology” Proc. Natl. Acad. Sci.83, 4913-4917
30. 30. Li C., Götz J., 2017. “Tau-based therapies in neurodegeneration: opportunities and challenges” Nature Reviews Drug Discovery 16, 863–883.
31. 31. Anand K, Sabbagh M., 2015. “Early investigational drugs targeting tau protein for the treatment of Alzheimer's disease” . Expert Opin Investig Drugs 24(10):1355–1360
32. 32. Baddeley T.C., McCaffrey J., Storey J.M.D., Cheung J.K.S., Melis V., Horsley D., Harrington C.R., Wischik C.M., 2015. “Complex Disposition of Methylthioninium Redox Forms Determines Efficacy in Tau Aggregation Inhibitor Therapy for Alzheimer’s Disease” J Pharmacol Exp Ther 352:110–118
33. 33. Song GJ., Suk K., 2017. “Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases”Front Aging Neurosci9: 139. doi: 10.3389/fnagi.2017.00139
34. 34. J., Michelle L., 2012. “Targeting Microglia-Mediated Neurotoxicity: The Potential of NOX2 Inhibitors” Cell Mol Life Sci. 69(14): 2409–2427
35. 35. Tanveer R., McGuinness N., Daniel S., Campbell A.G.V.A., 2012. “Cannabinoid receptors and neurodegenerative diseases” WIREs Membr Transp Signal 1:633–639.
36. 36. Cummings JL, Morstorf T, Zhong K, 2014. “Alzheimer's disease drug-development pipeline: few candidates, frequent failures”Alzheimers Res Ther. 6(4):37.