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Psychopharmacology

, Volume 233, Issue 4, pp 599–613 | Cite as

A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves Aβ25–35-impaired mouse cognitive function

  • Zhengping Zhang
  • Rong Chen
  • Wenji An
  • Chunmei Wang
  • Gaoyong Liao
  • Xiaoliang Dong
  • Aijing Bi
  • Zhimin Yin
  • Lan Luo
Original Investigation

Abstract

Rationale

The mechanism involved in AD is complex, which has prompted to develop compounds that could simultaneously interact with several potential targets. Here, we report a new synthesized compound SCR-1693 which is designed to target both AChE and calcium channels that are potential for AD therapy.

Objectives

We investigated the effects of SCR-1693 on AChE and calcium channels, the effects of neuroprotection and anti-amnesia in icv-Aβ25–35-injected mice, and the potential mechanisms.

Methods

AChE activity assay, intracellular Ca2+ content and calcium currents measurement, and Aβ25–35-induced cellular death determine were performed for validation of designed targets and neuroprotection of SCR-1693. Mice were orally administrated with SCR-1693 once daily after an Aβ25–35 injection. The Morris water maze and Y-maze test, and hippocampal protein detection were conducted on days 5–10, day 11, and day 8. The pyramidal neuron number, hippocampal AChE activity, and synaptic transmission were measured on day 12.

Results

SCR-1693 acted as a selective, reversible, and noncompetitive inhibitor of AChE, and a nonselective voltage-gated calcium channel blocker. SCR-1693 also inhibited the increase of AChE activity in the mouse hippocampus. SCR-1693 was more effective than donepezil and memantine in preventing Aβ25–35-induced long-term and short-term memory impairment, maintaining the basal transmission of Schaffer collateral-CA1 synapses, and sustaining LTP in mouse hippocampus. SCR-1693 attenuated Aβ25–35-induced death of SH-SY5Y cell and the loss of hippocampal pyramidal neurons, and regulated Aβ25–35-induced signal cascade in neurons.

Conclusions

All these findings indicated that SCR-1693, as a double-target-direction agent, is a considerable candidate for AD therapy.

Keywords

SCR-1693 AChE inhibitor VGCCs blocker Neuroprotection β-Amyloid Learning and memory 

Abbreviations

Amyloid β-peptide

25–35

Amyloid β25–35 peptide

AChE

Acetylcholinesterase

AD

Alzheimer’s disease

BuChE

Butyrylcholinesterase

CCB

Calcium channel blocker

DHP

Dihydropyridine

fEPSP

Field excitatory postsynaptic potential

icv

Intracerebroventricular

LTP

Long-term potentiation

NMDAR

N-Methyl-d-aspartate receptor

THA

Tetrahydroaminoacridine

VGCC

Voltage-gated calcium channel

Notes

Acknowledgments

This work was supported by Jiangsu Simovay Pharmaceutical Co., Ltd (Nanjing, China) and the grant from the National Natural Science Foundation of China (No. 81471557).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

213_2015_4133_MOESM1_ESM.docx (35 kb)
ESM 1 (DOC 35 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Zhengping Zhang
    • 1
    • 2
  • Rong Chen
    • 2
  • Wenji An
    • 2
  • Chunmei Wang
    • 2
  • Gaoyong Liao
    • 2
  • Xiaoliang Dong
    • 1
  • Aijing Bi
    • 1
  • Zhimin Yin
    • 3
  • Lan Luo
    • 1
  1. 1.State Key Laboratory of Pharmaceutical Biotechnology, School of Life SciencesNanjing UniversityNanjingPeople’s Republic of China
  2. 2.Jiangsu Simovay Pharmaceutical Co., Ltd.NanjingPeople’s Republic of China
  3. 3.Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life ScienceNanjing Normal UniversityNanjingPeople’s Republic of China

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