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Protective Effects of Flavonoid Rutin Against Aminochrome Neurotoxicity

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Abstract

Causes of dopaminergic neuronal loss in Parkinson’s disease (PD) are subject of investigation and the common use of models of acute neurodegeneration induced by neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine, and rotenone contributed to advances in the study of PD. However, the use of study models more similar to the pathophysiology of PD is required for advances in early diagnosis and translational pharmacology. Aminochrome (AMI), a compound derived from dopamine oxidation and a precursor of neuromelanin, is able to induce all the mechanisms associated with neurodegeneration. Previously, we showed AMI is cytotoxic in primary culture of mesencephalic cells (PCMC) and induces in vitro and in vivo neuroinflammation. On the other hand, the effect of rutin in central nervous system cells has revealed anti-inflammatory, antioxidative, and neuroprotective potential. However, there have been no data studies on the effect of rutin against aminochrome neurotoxicity. Here, we show that rutin prevents lysosomal dysfunction and aminochrome-induced cell death in SHSY-5Y cells, protects PCMC against aminochrome cytotoxicity, and prevents in vivo loss of dopaminergic neurons in substantia nigra pars compacta (SNPc), as well as microgliosis and astrogliosis. Additionally, we show that rutin decreases levels of interleukin-1β (IL-1β) mRNA and increases levels of glia-derived neurotrophic factor (GDNF) and nerve-derived neurotrophic factor (NGF) mRNA. We evidence for the first time the protective effect of rutin on PD aminochrome-induced models and suggest the potential role of the anti-inflammatory activity and upregulation of NGF and GDNF in the mechanism of rutin action against aminochrome neurotoxicity.

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Data availability

The datasets used and analyzed in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to the Postgraduate Program in Immunology at the Federal University of Bahia. We are thankful to Biorender for the design of the figures. We acknowledge the collaboration of the Master’s degree student Martinho Vaz Martinho in performing the dopamine and aminochrome HPLC analysis.

Funding

F.M.A., C.C.S., M.T.H., and J.S.A. were supported by grants from the Coordenação de Apoio de Pessoal de Nível Superior (PDSE-47/2017; CAPES/PVE– 189576/09–2014; PVB CAPES-PRINT/UFBA 2021); V.D.A.S. and S.L.C. were supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ Edital Universal/2018—429127/2018–9, 402051/2022–0, and Research Fellowship). L.C.B. thanks the Spanish Ministry of Science, Innovation and Universities (FPU 18/02549) for its support; M.T.H. thanks the Federación Española de Parkinson (FIS PI13 01293) and the Fundación Séneca (19540/PI/14) for its support; V.D.A.S. and S.L.C. thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ E. Universal/2018—429127/2018–9; and CNPQ—Research Fellowship) for its support.

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Authors and Affiliations

  1. Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Salvador, Brazil

    Fillipe Mendes De Araújo, Annyta F. Frota, Lívia B. de Jesus, Kariny Maria S. Ferreira, Cleonice Creusa Santos, Erica N. Soares, Jéssica T. Souza, Flávia S. Sanches, Ana Carla S. Costa, Alana A. Farias, Maria de Fatima Dias Costa, Silvia Lima Costa & Victor Diogenes Amaral Silva

  2. Clinical & Experimental Neuroscience (NiCE). Institute for Bio-Health Research of Murcia (IMIB), Institute for Aging Research (IUIE), School of Medicine, Campus Mare Nostrum, University of Murcia, Murcia, Spain

    Fillipe Mendes De Araújo, Lorena Cuenca-Bermejo & Maria Trinidad Herrero

  3. Instituto de Ciencias Biomedicas, Faculdad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile

    Patrícia Munoz

  4. Molecular & Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia, 1027, Santiago, Chile

    Patrícia Munoz & Juan Segura-Aguilar

  5. Graduate Program in Pharmacy, College of Pharmacy, Federal University of Bahia, Salvador, Brazil

    José A. Menezes-Filho

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  1. Fillipe Mendes De Araújo
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  2. Annyta F. Frota
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Contributions

V.D.A.S., M.T.H., and J.S.A. made the conception and design of the study; F.M.A, A.F., L.B.J., L.C.B., K.F., C.C.S., E.N.S., J.T.S., F.S., A.C.S.C., A.A.F. P.M., and J.A.M.F. were in charge of the acquisition of data; V.D.A.S., M.T.H., J.S.A., S.L.C., M.F.D.C., and J.A.M.F. made the analysis and the interpretation of the data; V.D.A.S., M.T.H., and J.S.A. made the draft of the article or critical review for important intellectual content.

Corresponding authors

Correspondence to Maria Trinidad Herrero or Victor Diogenes Amaral Silva.

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All procedures were approved by the Animal Use Ethics Committee of the Federal University of Bahia (CEUA/UFBA-Protocol n° 127/2017 and 011/2017).

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De Araújo, F.M., Frota, A.F., de Jesus, L.B. et al. Protective Effects of Flavonoid Rutin Against Aminochrome Neurotoxicity. Neurotox Res 41, 224–241 (2023). https://doi.org/10.1007/s12640-022-00616-1

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