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Combination therapy with cilostazol, aripiprazole, and donepezil protects neuronal cells from β-amyloid neurotoxicity through synergistically enhanced SIRT1 expression.
Korean J Physiol Pharmacol. 2020 Jul 01; 24(4):299-310.KJ

Abstract

Alzheimer's disease (AD) is a multi-faceted neurodegenerative disease. Thus, current therapeutic strategies require multitarget-drug combinations to treat or prevent the disease. At the present time, single drugs have proven to be inadequate in terms of addressing the multifactorial pathology of AD, and multitarget-directed drug design has not been successful. Based on these points of views, it is judged that combinatorial drug therapies that target several pathogenic factors may offer more attractive therapeutic options. Thus, we explored that the combination therapy with lower doses of cilostazol and aripiprazole with add-on donepezil (CAD) might have potential in the pathogenesis of AD. In the present study, we found the superior efficacies of donepezil add-on with combinatorial mixture of cilostazol plus aripiprazole in modulation of expression of AD-relevant genes: Aβ accumulation, GSK-3β, P300, acetylated tau, phosphorylated-tau levels, and activation of α-secretase/ADAM 10 through SIRT1 activation in the N2a Swe cells expressing human APP Swedish mutation (N2a Swe cells). We also assessed that CAD synergistically raised acetylcholine release and choline acetyltransferase (CHAT) expression that were declined by increased β-amyloid level in the activated N2a Swe cells. Consequently, CAD treatment synergistically increased neurite elongation and improved cell viability through activations of PI3K, BDNF, β-catenin and a7-nicotinic cholinergic receptors in neuronal cells in the presence of Aβ1-42. This work endorses the possibility for efficient treatment of AD by supporting the synergistic therapeutic potential of donepezil add-on therapy in combination with lower doses of cilostazol and aripiprazole.

Authors+Show Affiliations

Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea. Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan 50612, Korea.Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea. Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan 50612, Korea.Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea. Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan 50612, Korea.Department of Korean Medical Science, Pusan National University School of Korean Medicine, Yangsan 50612, Korea.Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan 50612, Korea.Department of Pharmacology, Pusan National University School of Medicine, Yangsan 50612, Korea. Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan 50612, Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32587124

Citation

Heo, Hye Jin, et al. "Combination Therapy With Cilostazol, Aripiprazole, and Donepezil Protects Neuronal Cells From Β-amyloid Neurotoxicity Through Synergistically Enhanced SIRT1 Expression." The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, vol. 24, no. 4, 2020, pp. 299-310.
Heo HJ, Park SY, Lee YS, et al. Combination therapy with cilostazol, aripiprazole, and donepezil protects neuronal cells from β-amyloid neurotoxicity through synergistically enhanced SIRT1 expression. Korean J Physiol Pharmacol. 2020;24(4):299-310.
Heo, H. J., Park, S. Y., Lee, Y. S., Shin, H. K., Hong, K. W., & Kim, C. D. (2020). Combination therapy with cilostazol, aripiprazole, and donepezil protects neuronal cells from β-amyloid neurotoxicity through synergistically enhanced SIRT1 expression. The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, 24(4), 299-310. https://doi.org/10.4196/kjpp.2020.24.4.299
Heo HJ, et al. Combination Therapy With Cilostazol, Aripiprazole, and Donepezil Protects Neuronal Cells From Β-amyloid Neurotoxicity Through Synergistically Enhanced SIRT1 Expression. Korean J Physiol Pharmacol. 2020 Jul 1;24(4):299-310. PubMed PMID: 32587124.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combination therapy with cilostazol, aripiprazole, and donepezil protects neuronal cells from β-amyloid neurotoxicity through synergistically enhanced SIRT1 expression. AU - Heo,Hye Jin, AU - Park,So Youn, AU - Lee,Yi Sle, AU - Shin,Hwa Kyoung, AU - Hong,Ki Whan, AU - Kim,Chi Dae, PY - 2019/12/20/received PY - 2020/03/12/revised PY - 2020/03/23/accepted PY - 2020/6/27/entrez PY - 2020/6/27/pubmed PY - 2020/6/27/medline KW - Alzheimer’s disease KW - Aripiprazole KW - Cilostazol KW - Donepezil KW - β-amyloid SP - 299 EP - 310 JF - The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology JO - Korean J. Physiol. Pharmacol. VL - 24 IS - 4 N2 - Alzheimer's disease (AD) is a multi-faceted neurodegenerative disease. Thus, current therapeutic strategies require multitarget-drug combinations to treat or prevent the disease. At the present time, single drugs have proven to be inadequate in terms of addressing the multifactorial pathology of AD, and multitarget-directed drug design has not been successful. Based on these points of views, it is judged that combinatorial drug therapies that target several pathogenic factors may offer more attractive therapeutic options. Thus, we explored that the combination therapy with lower doses of cilostazol and aripiprazole with add-on donepezil (CAD) might have potential in the pathogenesis of AD. In the present study, we found the superior efficacies of donepezil add-on with combinatorial mixture of cilostazol plus aripiprazole in modulation of expression of AD-relevant genes: Aβ accumulation, GSK-3β, P300, acetylated tau, phosphorylated-tau levels, and activation of α-secretase/ADAM 10 through SIRT1 activation in the N2a Swe cells expressing human APP Swedish mutation (N2a Swe cells). We also assessed that CAD synergistically raised acetylcholine release and choline acetyltransferase (CHAT) expression that were declined by increased β-amyloid level in the activated N2a Swe cells. Consequently, CAD treatment synergistically increased neurite elongation and improved cell viability through activations of PI3K, BDNF, β-catenin and a7-nicotinic cholinergic receptors in neuronal cells in the presence of Aβ1-42. This work endorses the possibility for efficient treatment of AD by supporting the synergistic therapeutic potential of donepezil add-on therapy in combination with lower doses of cilostazol and aripiprazole. SN - 1226-4512 UR - https://www.unboundmedicine.com/medline/citation/32587124/Combination_therapy_with_cilostazol,_aripiprazole,_and_donepezil_protects_neuronal_cells_from_β-amyloid_neurotoxicity_through_synergistically_enhanced_SIRT1_expression L2 - http://www.kjpp.net/journal/viewJournal.html?year=2020&vol=24&page=299 DB - PRIME DP - Unbound Medicine ER -
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