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

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF ALZHEIMER'S DISEASE; v. 78, n. 1, p. 353-370, 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 18/21709-1 - Efeitos neuroprotetores de novos compostos sintéticos (inibidores de colinesterases) em resposta a estímulos neurotóxicos e ao estresse oxidativo em células neuronais e astrocíticas
• Beneficiário: Elza Tiemi Sakamoto Hojo
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/15123-1 - Efeito protetor de inibidores de acetilcolinesterase em resposta a estímulos neurotóxicos e ao estresse oxidativo induzidos pelo peptídeo b-amiloide em linhagens neuronais SH-SY5Y e ACBRI-371
• Beneficiário: Natália Chermont dos Santos Moreira
• Modalidade de apoio: Bolsas no Brasil - Mestrado