Novel Multipotent AChEI-CCB Attenuates Hyperhomocysteinemia-Induced Memory Deficits and Neuropathologies in Rats

Article type: Research Article

Authors: Xia, Yiyuan^a | Liu, Rong^a | Chen, Rong^b | Tian, Qing^a | Zeng, Kuan^a | Hu, Jichang^a | Liu, Xinghua^a | Wang, Qun^a | Wang, Peng^c | Wang, Xiao-Chuan^{a; *} | Wang, Jian-Zhi^{a; *}

Affiliations: [a] Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [b] Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, China | [c] Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China

Correspondence: [*] Correspondence to: Jian-Zhi Wang and Xiao-Chuan Wang, Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Tel.: +086 27 83692625; Fax: +086 27 83693883; E-mails: [email protected]; [email protected].

Abstract: Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3β. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD.

Keywords: Alzheimer's disease, GSK-3β, hyperhomocysteinemia, PP2A, SCR1693, tau

DOI: 10.3233/JAD-140597

Journal: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 1029-1039, 2014