Advanced search
Start date
Betweenand

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

Grant number: 17/15123-1
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2018
Effective date (End): February 28, 2019
Field of knowledge:Biological Sciences - Genetics
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Elza Tiemi Sakamoto Hojo
Grantee:Natália Chermont dos Santos Moreira
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Alzheimer's disease (AD), characterized by a progressive episodic memory loss, is a cerebral disorder caused by the B-amyloid peptide (AB) deposits (senile plaques) and abnormal tau protein phosphorylation (neurofibrillary tangles) in the brain and therefore, loss of cholinergic function of the central nervous system. It is well known that the impairment of this function due to AB neurotoxicity significantly contributes to cognitive decline associated with AD. Inhibitors of the enzyme acetylcholinesterase (AChE), such as tacrine and donepezil drugs, are the main drugs used in the clinic for the treatment of AD. There is a great need for the synthesis of new molecules, since the drugs already in use by the patients presented high hepatic toxicity, proven in the literature, besides several side effects (such as nausea, vomiting and diarrhea) due to the action in the peripheral tissues . Thus, it becomes extremely necessary to obtain molecules of high efficiency and are at risk and devoid of side effects to patients. Thus, one hypothesis of the present project is based on the study of hybrid compounds of AChE-inhibited donepezil-tacrine, synthesized based on the three-dimensional structure thereof. The neuron SH-SY5Y (Chierrito et al., Eur J Med), neuro-vivifying and neuroproduction, in addition to the ability to induce neurodifferentiation in SH-SY5Y neuronal lineage (Chierrito et al., Eur J Med Chem. October, 139: 773-791). The present study aimed to evaluate the neuroprotective capacity of new compounds that are acetylcholinesterase inhibitors (AChEI), designated TA8Amino, TAHB3 and TA7E3, tested in SH-SY5Y and ACBRI-371 neuronal cell lines, in response to neurotoxic damage induced by the AB (1-42). In this context, cell viability, clonogenic survival, death and cell cycle assays were performed to evaluate cytotoxicity in response to the treatments used. There will be also molecular markers of differentiation (such as B-III-tubulin, MAP2 and pNF-M) of SH-SY5Y cell lines in mature neurons; in addition, it will be evaluated: mitochondrial dysfunction, reactive oxygen species (ROS) production, membrane potential, morphology and mitochondrial mass. Besides, it will be analyzed the ability of AChEI compounds to act to protect cells against genotoxic damage caused by the AB peptide (1-42), which is evaluated by micronucleus and comet assays. Since preliminary studies indicate a promise of neuroprotection activity of AChEI compounds, it is expected that the present study could generate relevant information about the potential of these molecules as new drugs for the treatment of patients with AD. (AU)