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

A new human pyridinium metabolite of furosemide, inhibitor of mitochondrial complex I, is a candidate inducer of neurodegeneration. Biochem Pharmacol. 2018 Dec 08;: Authors: Laurencé C, Zeghbib N, Rivard M, Lehri-Boufala S, Lachaise I, Barau C, Le Corvoisier P, Martens T, Garrigue-Antar L, Morin C 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...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research