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 Ca(2+) 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.

journal_title

Psychopharmacology

authors

Zhang Z,Chen R,An W,Wang C,Liao G,Dong X,Bi A,Yin Z,Luo L

doi

10.1007/s00213-015-4133-5

subject

Has Abstract

pub_date

2016-02-01 00:00:00

pages

599-613

issue

4

eissn

0033-3158

issn

1432-2072

pii

10.1007/s00213-015-4133-5

journal_volume

233

pub_type

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