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

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.

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Abbreviations

Aβ:

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

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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).

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Correspondence to Zhimin Yin or Lan Luo.

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Zhang, Z., Chen, R., An, W. et al. A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves Aβ25–35-impaired mouse cognitive function. Psychopharmacology 233, 599–613 (2016). https://doi.org/10.1007/s00213-015-4133-5

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Keywords

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