Novel Dual AChE and ROCK2 Inhibitor Induces Neurogenesis via PTEN/AKT Pathway in Alzheimer's Disease Model

Autor(es)

Moreira, Natalia Chermont dos Santos ; Tamarozzi, Elvira Regina ; Lima, Jessica Ellen Barbosa de Freitas ; Piassi, Larissa de Oliveira ; Carvalho, Ivone ; Passos, Geraldo Aleixo ; Sakamoto-Hojo, Elza Tiemi

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 23, n. 23, p. 22-pg., 2022-12-01.

Resumo

Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease. Acetylcholinesterase inhibitors (AChEIs) are a major class of drugs used in AD therapy. ROCK2, another promising target for AD, has been associated with the induction of neurogenesis via PTEN/AKT. This study aimed to characterize the therapeutic potential of a novel donepezil-tacrine hybrid compound (TA8Amino) to inhibit AChE and ROCK2 protein, leading to the induction of neurogenesis in SH-SY5Y cells. Experiments were carried out with undifferentiated and neuron-differentiated SH-SY5Y cells submitted to treatments with AChEIs (TA8Amino, donepezil, and tacrine) for 24 h or 7 days. TA8Amino was capable of inhibiting AChE at non-cytotoxic concentrations after 24 h. Following neuronal differentiation for 7 days, TA8Amino and donepezil increased the percentage of neurodifferentiated cells and the length of neurites, as confirmed by beta-III-tubulin and MAP2 protein expression. TA8Amino was found to participate in the activation of PTEN/AKT signaling. In silico analysis showed that TA8Amino can stably bind to the active site of ROCK2, and in vitro experiments in SH-SY5Y cells demonstrate that TA8Amino significantly reduced the expression of ROCK2 protein, contrasting with donepezil and tacrine. Therefore, these results provide important information on the mechanism underlying the action of TA8Amino with regard to multi-target activities. (AU)

• 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
• 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