Novel Hybrid Acetylcholinesterase Inhibitors Induce Differentiation and Neuritogenesis in Neuronal Cells in vitro Through Activation of the AKT Pathway

Article type: Research Article

Authors: Moreira, Natália Chermont dos Santos^a | Lima, Jéssica Ellen Barbosa de Freitas^a | Chierrito, Talita Perez Cantuaria^c | Carvalho, Ivone^c | Sakamoto-Hojo, Elza Tiemi^{a; b; *}

Affiliations: [a] Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil | [b] Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil | [c] School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

Correspondence: [*] Correspondence to: Elza T. Sakamoto-Hojo, Department of Biology–Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo–USP, Ribeirão Preto, SP; Av. Bandeirantes, 3900–Monte Alegre 14040-901–Ribeirão Preto, S.P., Brazil. Tel.: +55 16 3315 3827; Fax: +55 16 3315 0222; E-mail: etshojo@usp.br.

Abstract: Background:Alzheimer’s disease (AD) is characterized by a progressive loss of episodic memory associated with amyloid-β peptide aggregation and the abnormal phosphorylation of the tau protein, leading to the loss of cholinergic function. Acetylcholinesterase (AChE) inhibitors are the main class of drugs used in AD therapy. Objective:The aim of the current study was to evaluate the potential of two tacrine-donepezil hybrid molecules (TA8Amino and TAHB3), which are AChE inhibitors, to induce neurodifferentiation and neuritogenesis in SH-SY5Y cells. Methods:The experiments were carried out to characterize neurodifferentiation, cellular changes related to responses to oxidative stress and pathways of cell survival in response to drug treatments. Results:The results indicated that the compounds did not present cytotoxic effects in SH-SY5Y or HepG2 cells. TA8Amino and TAHB3 induced neurodifferentiation and neuritogenesis in SH-SY5Y cells. These cells showed increased levels of intracellular and mitochondrial reactive oxygen species; the induction of oxidative stress was also demonstrated by an increase in SOD1 expression in TA8Amino and TAHB3-treated cells. Cells treated with the compounds showed an increase in PTEN(Ser380/Thr382/383) and AKT(Ser473) expression, suggesting the involvement of the AKT pathway. Conclusion:Our results demonstrated that TA8Amino and TAHB3 present advantages as potential drugs for AD therapy and that they are capable of inducing neurodifferentiation and neuritogenesis.

Keywords: Acetylcholinesterase inhibitors, AKT pathway, Alzheimer’s disease, neuronal differentiation, oxidative stress, SH-SY5Y cells

DOI: 10.3233/JAD-200425

Journal: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 353-370, 2020