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

Author(s)

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

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 23, n. 23, p. 22-pg., 2022-12-01.

Abstract

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)

• 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
• 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