Accéder directement au contenu Accéder directement à la navigation
Article dans une revue

A new human pyridinium metabolite of furosemide, inhibitor of mitochondrial complex I, is a candidate inducer of neurodegeneration

Abstract : Pharmaceuticals and their by-products are increasingly a matter of concern, because of their unknown impacts on human health and ecosystems. The lack of information on these transformation products, which toxicity may exceed that of their parent molecules, makes their detection and toxicological evaluation impossible. Recently we characterized the Pyridinium of furosemide (PoF), a new transformation product of furosemide, the most widely used diuretic and an emerging pollutant. Here, we reveal PoF toxicity in SH-SY5Y cells leading to alpha-synuclein accumulation, reactive oxygen species generation, and apoptosis. We also showed that its mechanism of action is mediated through specific inhibition of striatal respiratory chain complex I, both in vitro by direct exposure of striatum mitochondria to PoF, and in vivo, in striatal mitochondria isolated from mice exposed to PoF for 7 days in drinking water and sacrificed 30 days later. Moreover, in mice, PoF induced neurodegenerative diseases hallmarks like phospho-Serine129 alpha-synuclein, tyrosine hydroxylase decrease in striatum, Tau accumulation in hippocampus. Finally, we uncovered PoF as a new metabolite of furosemide present in urine of patients treated with this drug by LC/MS. As a physiopathologically relevant neurodegeneration inducer, this new metabolite warrants further studies in the framework of public health and environment protection.
Liste complète des métadonnées

https://hal-enpc.archives-ouvertes.fr/hal-02267947
Contributeur : Christophe Morin <>
Soumis le : mardi 20 août 2019 - 09:33:22
Dernière modification le : samedi 19 septembre 2020 - 03:47:32

Identifiants

Citation

Céline Laurencé, Narimane Zeghbib, Michael Rivard, Sonia Lehri-Boufala, Isabelle Lachaise, et al.. A new human pyridinium metabolite of furosemide, inhibitor of mitochondrial complex I, is a candidate inducer of neurodegeneration. Biochemical Pharmacology, Elsevier, 2019, 160, pp.14-23. ⟨10.1016/j.bcp.2018.12.007⟩. ⟨hal-02267947⟩

Partager

Métriques

Consultations de la notice

156