Neuroprotective Effect of a New 7,8-Dihydroxycoumarin-Based Fe2+/Cu2+ Chelator in Cell and Animal Models of Parkinson?s Disease

dc.creatorAguirre, Pabla
dc.creatorGarc?a-Beltr?n, Olimpo
dc.creatorTapia, Victoria
dc.creatorMu?oz, Yorka
dc.creatorCassels, Bruce K.
dc.creatorN??ez, Marco T.
dc.date2019-03-11T16:23:33Z
dc.date2019-03-11T16:23:33Z
dc.date2017-01-18
dc.date.accessioned2023-08-31T19:21:39Z
dc.date.available2023-08-31T19:21:39Z
dc.identifierAguirre, P., Garc?a-Beltr?n, O., Tapia, V., Mu?oz, Y., Cassels, B. K., & N??ez, M. T. (2017). Neuroprotective Effect of a New 7,8-Dihydroxycoumarin-Based Fe2+/Cu2+ Chelator in Cell and Animal Models of Parkinson?s Disease. ACS Chemical Neuroscience, 8(1), 178?185.
dc.identifier1948-7193
dc.identifierhttps://pubs.acs.org/doi/10.1021/acschemneuro.6b00309
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8557337
dc.descriptionDisturbed iron homeostasis, often coupled to mitochondrial dysfunction, plays an important role in the progression of common neurodegenerative diseases such as Parkinson?s disease (PD). Recent studies have underlined the relevance of iron chelation therapy for the treatment of these diseases. Here we describe the synthesis, chemical, and biological characterization of the multifunctional chelator 7,8-dihydroxy-4-((methylamino)methyl)-2H-chromen-2-one (DHC12). Metal selectivity of DHC12 was Cu2+ ? Fe2+ > Zn2+ > Fe3+. No binding capacity was detected for Hg2+, Co2+, Ca2+, Mn2+, Mg2+, Ni2+, Pb2+, or Cd2+. DHC12 accessed cells colocalizing with Mitotracker Orange, an indication of mitochondrial targeting. In addition, DHC12 chelated mitochondrial and cytoplasmic labile iron. Upon mitochondrial complex I inhibition, DHC12 protected plasma membrane and mitochondria against lipid peroxidation, as detected by the reduced formation of 4-hydroxynonenal adducts and oxidation of C11-BODIPY581/591. DHC12 also blocked the decrease in mitochondrial membrane potential, detected by tetramethylrhodamine distribution. DHC12 inhibited MAO-A and MAO-B activity. Oral administration of DHC12 to mice (0.25 mg/kg body weight) protected substantia nigra pars compacta (SNpc) neurons against MPTP-induced death. Taken together, our results support the concept that DHC12 is a mitochondrial-targeted neuroprotective iron?copper chelator and MAO-B inhibitor with potent antioxidant and mitochondria protective activities. Oral administration of low doses of DHC12 is a promising therapeutic strategy for the treatment of diseases with a mitochondrial iron accumulation component, such as PD.
dc.languageen
dc.publisherACS Chemical Neuroscience
dc.subjectAntioxidant
dc.subjectCoumarin-based iron?copper chelator
dc.subjectMPTP mouse model
dc.subjectNeurodegeneration with brain iron accumulation
dc.subjectNeuroprotection
dc.subjectParkinson's disease
dc.titleNeuroprotective Effect of a New 7,8-Dihydroxycoumarin-Based Fe2+/Cu2+ Chelator in Cell and Animal Models of Parkinson?s Disease
dc.typeArticle


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