New multifunctional AChE inhibitor drug prototypes protect against Aβ-induced memory deficit
Alzheimer’s disease (AD) is the most incident neurodegenerative disorder, characterized by accumulation of extracellular amyloid-β (Aβ), intracellular neurofibrillary tangles, and cognitive impairment. The current available treatments are mainly based on the use of reversible acetylcholinesterase (AChE) inhibitors, which only ameliorate the cognitive deficits. However, it is important to develop disease-modifying drugs with neuroprotective effects in order to hamper the progression of the disease. Here, we describe the effect of four promising new drugs with additional protective characteristics on AD-associated memory changes. C57Bl/6 mice treated with the compounds received an intra-hippocampal injection of Aβ1-40 and were submitted to the novel object recognition test, to evaluate memory recovery. All the compounds prevented memory loss. Compounds PQM-56 (4c) and PQM-67 (4g) showed the best profile of memory recovery, representing potential drug candidates for AD treatment.
KeywordsAlzheimer’s disease Amyloid-β Memory N-benzyl-piperidine-aryl-acylhydrazone derivatives
amyloid precursor protein
phosphate buffered saline
The authors are grateful to the Brazilian Agencies FINEP, INCT-INOFAR. ACPdO and CVJr acknowledge CNPq for the Research Productivity Fellowships.
F. P. D. V., M. de F. S., R. P. M., S. M. V., M. M. R., and C. V.J. conceived and synthesized the compounds. P. M. Q. B., A. C. C., W. de O. C.-J., I. V. de A. L., S. W. S., and G. V. performed the in vivo experiments. P. M. Q. B., C.V. Jr., and A.C.P. de O. wrote the paper with input from coauthors. All authors approved the final version of the manuscript. Paula M. Q. Bellozia, Alline C. Campos, and Antônio C. P. de Oliveira contributed equally to this work.
This work was supported by FAPEMIG (#CEX-PPM-00241-15 and #CBB-APQ-02044-15) and CNPq (CNPq #454088/2014-0, #400271/2014-1, #424588-2016-1 and # 406739/2018–8). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance Code 001.
Compliance with ethical standards
All the procedures with animals used in this study were institutionally approved by the Ethic Committee on Animal Use and followed the National Institutes of Health guide for the care and use of laboratory animals.
Conflict of interest
The authors declare that they have no conflict of interest.
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