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Genistein and Galantamine Combinations Decrease β-Amyloid Peptide (1–42)–Induced Genotoxicity and Cell Death in SH-SY5Y Cell Line: an In Vitro and In Silico Approach for Mimic of Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is the primary dementia-causing disease worldwide, involving a multifactorial combination of environmental, genetic, and epigenetic factors, with essential participation of age and sex. Biochemically, AD is characterized by the presence of abnormal deposition of beta amyloid peptide (Aβ(1–42)), which in the brain is strongly correlated with oxidative stress, inflammation, DNA damage, and cholinergic impairment. The multiple mechanisms involved in its etiology create significant difficulty in producing an effective treatment. Neuroprotective properties of genistein and galantamine have been widely demonstrated through different mechanisms; however, it is unknown a possible synergistic neuroprotective effect against Aβ(1–42). In order to understand how genistein and galantamine combinations regulate the mechanisms of neuroprotection, we conducted a set of bioassays in vitro to evaluate cell viability, clonogenic survival, cell death, and anti-genotoxicity. Through molecular docking and therapeutic viability assays, we analyzed the inhibitory activity exerted by genistein on three major protein targets (AChE, BChE, and NMDA) involved in AD. The results showed that genistein and galantamine afforded significant protection at higher concentrations; however, combinations of sub-effective concentrations of both compounds provided marked neuroprotection when they were combined. In silico approaches showed that genistein has higher scores than the positive controls and low toxicity levels; nevertheless, the therapeutic viability indicated that unlike galantamine, genistein cannot undergo the action by P glycoprotein (PGP) and probably may be unable to cross the blood-brain barrier. In conclusion, our results show that genistein and galantamine exert neuroprotective by decreasing genotoxicity and cell death. In silico analysis, suggest that genistein modulates positively the expression of AChE, BChE, and NMDA. In this context, a combination of two or more drugs could inspire an attractive therapeutic strategy.

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Authors and Affiliations

  1. Department of Biology, Faculty of Natural Sciences and Education, University of Cauca, Cra 2 No 2N-57, Popayán, 19003, Colombia

    Willian Orlando Castillo & Nilza Velasco Palomino

  2. Department of Genetics, Ribeirão Preto Medical School, University of São Paulo—USP, Ribeirão Preto, 14090-900, Brazil

    Catarina Satie Takahashi & Silvana Giuliatti

  3. Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo—USP, Ribeirão Preto, Brazil

    Catarina Satie Takahashi

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  1. Willian Orlando Castillo
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  2. Nilza Velasco Palomino
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  3. Catarina Satie Takahashi
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  4. Silvana Giuliatti
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Correspondence to Willian Orlando Castillo.

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Castillo, W.O., Palomino, N.V., Takahashi, C.S. et al. Genistein and Galantamine Combinations Decrease β-Amyloid Peptide (1–42)–Induced Genotoxicity and Cell Death in SH-SY5Y Cell Line: an In Vitro and In Silico Approach for Mimic of Alzheimer’s Disease. Neurotox Res 38, 691–706 (2020). https://doi.org/10.1007/s12640-020-00243-8

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