The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Combination therapy with cilostazol, aripiprazole, and donepezil protects neuronal cells from β-amyloid neurotoxicity through synergistically enhanced SIRT1 expression

  • Heo, Hye Jin (Department of Pharmacology, Pusan National University School of Medicine) ;
  • Park, So Youn (Department of Pharmacology, Pusan National University School of Medicine) ;
  • Lee, Yi Sle (Department of Pharmacology, Pusan National University School of Medicine) ;
  • Shin, Hwa Kyoung (Department of Korean Medical Science, Pusan National University School of Korean Medicine) ;
  • Hong, Ki Whan (Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University) ;
  • Kim, Chi Dae (Department of Pharmacology, Pusan National University School of Medicine)
  • Received : 2019.12.20
  • Accepted : 2020.03.23
  • Published : 2020.07.01
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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 α7-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.

Keywords

Acknowledgement

This study was supported by a 2-Year Research Grant of Pusan National University, Republic of Korea.

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