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

Author(s)

dos Santos Moreira, Natalia Chermont ^[1] ; Barbosa de Freitas Lima, Jessica Ellen ^[1] ; Cantuaria Chierrito, Talita Perez ^[2] ; Carvalho, Ivone ^[2] ; Sakamoto-Hojo, Elza Tiemi ^{[1, 3]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Biol, Av Bandeirantes 3900, BR-14040901 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF ALZHEIMER'S DISEASE; v. 78, n. 1, p. 353-370, 2020.
• Web of Science Citations: 0

Abstract

Background: Alzheimer's disease (AD) is characterized by a progressive loss of episodic memory associated with amyloid-beta 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. (AU)

• FAPESP's process: 18/21709-1 - Neuroprotective effects of novel synthetic compounds (cholinesterase inhibitors) in response to neurotoxic stimuli and oxidative stress in neuronal and astrocytic cells
• Grantee: Elza Tiemi Sakamoto Hojo
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/15123-1 - Protective effect of acetylcholinesterase inhibitors in response to neurotoxic stimuli and oxidative stress induced by B-amyloid peptide in neuronal SH-SY5Y and ACBRI-371 cell lines
• Grantee: Natália Chermont dos Santos Moreira
• Support Opportunities: Scholarships in Brazil - Master