Neuroprotective Effect of a New 7,8-Dihydroxycoumarin-Based Fe2+/Cu2+Chelator in Cell and Animal Models of Parkinson's Disease.
Disturbed 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.
Biology Department, Faculty of Sciences, Universidad de Chile , Santiago 7800024, Chile.
Pabla
P
Aguirre
Facultad de Ciencias Naturales y Matemáticas, Universidad de Ibagué , Ibagué 730001, Colombia.
Olimpo
O
García-Beltrán
Biology Department, Faculty of Sciences, Universidad de Chile , Santiago 7800024, Chile.
Victoria
V
Tapia
Biology Department, Faculty of Sciences, Universidad de Chile , Santiago 7800024, Chile.
Yorka
Y
Muñoz
Department of Chemistry, Faculty of Sciences, Universidad de Chile , Santiago 7800024, Chile.
Bruce K
BK
Cassels
Biology Department, Faculty of Sciences, Universidad de Chile , Santiago 7800024, Chile.
Marco T
MT
Núñez
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C000624285:7,8-dihydroxy-4-((methylamino)methyl)-2H-chromen-2-one; C114368:7,8-dihydroxy-4-methylcoumarin; D003374:Coumarins; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D003300:Copper; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007501:Iron; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase
MPTP mouse model; Neurodegeneration with brain iron accumulation; Parkinson;s disease; antioxidant; coumarin-based iron−copper chelator; neuroprotection