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New multifunctional AChE inhibitor drug prototypes protect against Aβ-induced memory deficit

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Abstract

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.

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Fig. 1
Fig. 2

Abbreviations

Aβ:

amyloid-β

AChE:

acetylcholinesterase

ACh:

acetylcholine

AD:

Alzheimer’s disease

APP:

amyloid precursor protein

NO:

new object

OO:

old object

PBS:

phosphate buffered saline

TBS:

tris-buffered saline

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Acknowledgments

The authors are grateful to the Brazilian Agencies FINEP, INCT-INOFAR. ACPdO and CVJr acknowledge CNPq for the Research Productivity Fellowships.

Funding

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.

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Author notes

  1. Paula M. Q. Bellozi, Alline C. Campos, Claudio Viegas Jr and Antônio C. P. de Oliveira contributed equally to this work.

Authors and Affiliations

  1. Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil

    Paula M. Q. Bellozi, Wellerson de O. Carneiro-Junior, Isabel V. de A. Lima, Soraya W. Saliba, Gabriela Neves Vaz & Antônio C. P. de Oliveira

  2. Department of Pharmacology, Federal University of de São Paulo, Ribeirão Preto, SP, 14049-900, Brazil

    Alline C. Campos

  3. Institute of Chemistry, Laboratory of Research on Medicinal Chemistry, Federal University of Alfenas, Alfenas, MG, 37133-840, Brazil

    Flávia P. D. Viegas, Matheus de F. Silva, Rafael P. Machado, Sarah M. Vaz, Mariana M. Riquiel & Claudio Viegas Jr

Authors
  1. Paula M. Q. Bellozi
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  2. Alline C. Campos
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  3. Flávia P. D. Viegas
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  4. Matheus de F. Silva
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  5. Rafael P. Machado
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  6. Sarah M. Vaz
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  7. Mariana M. Riquiel
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  8. Wellerson de O. Carneiro-Junior
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  9. Isabel V. de A. Lima
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  10. Soraya W. Saliba
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  11. Gabriela Neves Vaz
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  12. Claudio Viegas Jr
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  13. Antônio C. P. de Oliveira
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Contributions

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.

Corresponding authors

Correspondence to Claudio Viegas Jr or Antônio C. P. de Oliveira.

Ethics declarations

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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Electronic supplementary material

Experimental procedures: animals, drugs, treatment and surgery, object recognition task, statistical analysis.

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Bellozi, P.M.Q., Campos, A.C., Viegas, F.P.D. et al. New multifunctional AChE inhibitor drug prototypes protect against Aβ-induced memory deficit. Neurol Sci 41, 451–455 (2020). https://doi.org/10.1007/s10072-019-04036-6

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  • DOI: https://doi.org/10.1007/s10072-019-04036-6

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