title: Protective effects of synthetic kynurenines on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.
abstract: Mitochondrial complex I inhibition is thought to underlie the neurodegenerative process in Parkinson's disease (PD). Moreover, an overproduction of nitric oxide due to both cytosolic (iNOS) and mitochondrial (i-mtNOS) inducible nitric oxide synthases causes free radicals generation and oxidative/nitrosative stress, contributing to mitochondrial dysfunction and neuronal cell death. Looking for active molecules against mitochondrial dysfunction and inflammatory response in PD, we show here the effects of four synthetic kynurenines in the MPTP model of PD in mice. After MPTP administration, mitochondria from substantia nigra and, in a lesser extent, from striatum showed a significant increase in i-mtNOS activity, nitric oxide production, oxidative stress, and complex I inhibition. The four kynurenines assayed counteracted the effects of MPTP, reducing iNOS/i-mtNOS activity, and restoring the activity of the complex I. Consequently, the cytosolic and mitochondrial oxidative/nitrosative stress returned to control values. The results suggest that the kynurenines here reported represent a family of synthetic compounds with neuroprotective properties against PD, and that they can serve as templates for the design of new drugs able to target the mitochondria.
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain.
authors.forename: Dario
authors.initials: D
authors.lastname: Acuña-Castroviejo
authors.forename: Victor
authors.initials: V
authors.lastname: Tapias
authors.forename: Luis C
authors.initials: LC
authors.lastname: López
authors.forename: Carolina
authors.initials: C
authors.lastname: Doerrier
authors.forename: Encarnación
authors.initials: E
authors.lastname: Camacho
authors.forename: María D
authors.initials: MD
authors.lastname: Carrión
authors.forename: Francisco
authors.initials: F
authors.lastname: Mora
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
authors.forename: Germaine
authors.initials: G
authors.lastname: Escames
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism / Q000648:ultrastructure; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D007737:Kynurenine / Q000737:chemistry* / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D020267:MPTP Poisoning / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
chemical_list: D009573:Nitrites; D009243:NAD; D007737:Kynurenine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II