A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson's Disease.

Autor: Fouché B; Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa., Turner S; School of Life Sciences, University of Sussex, Falmer, Brighton, UK., Gorham R; School of Life Sciences, University of Sussex, Falmer, Brighton, UK., Stephenson EJ; School of Life Sciences, University of Sussex, Falmer, Brighton, UK., Gutbier S; Unit for In Vitro Toxicology and Biomedicine, Department Inaugurated By the Doeren Kamp-Zbinden Foundation, University of Konstanz, 78457, Konstanz, Germany., Elson JL; Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa.; The Welcome Trust Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK., García-Beltrán O; Centro Integrativo de Biología Y Química Aplicada, Universidad Bernardo O'Higgins, Santiago, Chile.; Facultad de Ciencias Naturales Y Matemáticas, Universidad de Ibagué, Ibagué, Colombia., Van Der Westhuizen FH; Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa., Pienaar IS; Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa. i.pienaar@bham.ac.uk.; Institute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham, B12 2TT, UK. i.pienaar@bham.ac.uk.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2023 Feb; Vol. 60 (2), pp. 749-767. Date of Electronic Publication: 2022 Nov 11.
DOI: 10.1007/s12035-022-03107-8
Abstrakt: Coumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson's disease (PD). Here we demonstrate the neuroprotective potential of a new polyhydroxyl coumarin, N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide (CT51), against the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP + ). MPP+'s mechanism of toxicity relates to its ability to inhibit complex I of the mitochondrial electron transport chain (METC), leading to adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death, hence mimicking PD-related neuropathology. Dopaminergic differentiated human neuroblastoma cells were briefly pretreated with CT51, followed by toxin exposure. CT51 significantly restored somatic cell viability and neurite processes; hence, the drug targets cell bodies and axons thereby preserving neural function and circuitry against PD-related damage. Moreover, MPP+ emulates the iron dyshomeostasis affecting dopaminergic neurons in PD-affected brains, whilst CT51 was previously revealed as an effective iron chelator that preferentially partitions to mitochondria. We extend these findings by characterising the drug's interactive effects at the METC level. CT51 did not improve mitochondrial coupling efficiency. However, voltammetric measurements and high-resolution respirometry analysis revealed that CT51 acts as an antioxidant agent. Also, the neuronal protection afforded by CT51 associated with downregulating MPP+-induced upregulated expression of hypoxia-inducible factor 1 alpha (HIF-1α), a protein which regulates iron homeostasis and protects against certain forms of oxidative stress after translocating to mitochondria. Our findings support the further development of CT51 as a dual functioning iron chelator and antioxidant antiparkinsonian agent.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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