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Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and β‐cyclodextrin nanoparticles

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Abstract

Niemann-Pick C disease (NPC) is an autosomal recessive genetic disorder resulting from mutation in one of two cholesterol transport genes: NPC1 or NPC2, causing accumulation of unesterified cholesterol, together with glycosphingolipids, within the endosomal/lysosomal compartment of cells. The result is a severe disease in both multiple peripheral organs and the central nervous system, causing neurodegeneration and early death. However, the pathophysiological mechanisms of NPC1 remain poorly understood. Recent studies have shown that the primary lysosomal defect found in fibroblasts from NPC1 patients is accompanied by a deregulation of mitochondrial organization and function. There is currently no cure for NPC1, but recently the potential of β-cyclodextrin (β-CD) for the treatment of the disease was discovered, which resulted in the redistribution of cholesterol from subcellular compartments to the circulation and increased longevity in an animal model of NPC1. Considering the above, the present work evaluated the in vitro therapeutic potential of β-CD to reduce cholesterol in fibroblasts from NPC1 patients. β-CD was used in its free and nanoparticulate form. We also evaluated the β-CD potential to restore mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidants N-Acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). Besides, we evaluated oxidative and nitrative stress parameters in NPC1 patients. We showed that oxidative and nitrative stress could contribute to the pathophysiology of NPC1, as the levels of lipoperoxidation and the nitrite and nitrate levels were increased in these patients when compared to healthy individuals, as well as DNA damage. The nanoparticles containing β-CD reduced the cholesterol accumulated in the NPC1 fibroblasts. This result was potentiated by the concomitant use of the nanoparticles with the antioxidants NAC and CoQ10 compared to those presented by healthy individuals cells ́. In addition, treatments combining β-CD nanoparticles and antioxidants could reduce mitochondrial oxidative stress, demonstrating advantages compared to free β-CD. The results obtained are promising regarding the combined use of β-CD loaded nanoparticles and antioxidants in the treatment of NPC1 disease.

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Acknowledgements

We would like to thank the patients and their families, as well as the medical staff of the for logistic and technical support in the developmental of this study.

Funding

This work was supported by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/MEC-Brasil); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/MCTI-Brasil number 430443/2018–8); Fundo de Incentivo à Pesquisa e Eventos (FIPE/HCPA – number 2018–0648).

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Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Tatiane Grazieli Hammerschmidt, Jéssica Lamberty Faverzani, Franciele de Fátima Lopes & Carmen R. Vargas

  2. Grupo Hospitalar Conceição, Porto Alegre, Brazil

    Bruna Donida

  3. Laboratório de Genética Toxicológica, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil

    Marco Raabe, Luiza S. Reinhardt & Dinara J. Moura

  4. Serviço de Genética Médica, HCPA, Rua Ramiro Barcelos, 2350, Porto Alegre, RS, CEP 90035-003, Brazil

    Franciele de Fátima Lopes, Andryele Z. Machado, Rejane G. Kessler & Carmen R. Vargas

  5. Priority Research Centre for Cancer Research, Innovation and Translation, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia

    Luiza S. Reinhardt

  6. Programa de Pós-Graduação em Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Fernanda Poletto

  7. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Fernanda Poletto & Carmen R. Vargas

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  1. Tatiane Grazieli Hammerschmidt
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  2. Bruna Donida
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Tatiane G Hammerschmidt, Bruna Donida, Marco Raabe, Jéssica L Faverzani, Andryele Z Machado, Rejane G Kessler, Luiza S Reinhardt, Fernanda Poletto and Dinara J Moura. The first draft of the manuscript was written by Tatiane G Hammerschmidt and Bruna Donida, as well as revised by Carmen R Vargas. All authors read and approved the final manuscript.

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Correspondence to Tatiane Grazieli Hammerschmidt or Carmen R. Vargas.

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Hammerschmidt, T.G., Donida, B., Raabe, M. et al. Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and β‐cyclodextrin nanoparticles. Metab Brain Dis 38, 507–518 (2023). https://doi.org/10.1007/s11011-022-01128-9

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