title: Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson's disease.
abstract: L-Dopa continues to be the gold drug in Parkinson's disease (PD) treatment from 1967. The failure to translate successful results from preclinical to clinical studies can be explained by the use of preclinical models which do not reflect what happens in the disease since these induce a rapid and extensive degeneration; for example, MPTP induces a severe Parkinsonism in only 3 days in humans contrasting with the slow degeneration and progression of PD. This study presents a new anatomy and develops preclinical model based on aminochrome which induces a slow and progressive dysfunction of dopaminergic neurons. The unilateral injection of aminochrome into rat striatum resulted in (1) contralateral rotation when the animals are stimulated with apomorphine; (2) absence of significant loss of tyrosine hydroxylase-positive neuronal elements both in substantia nigra and striatum; (3) cell shrinkage; (4) significant reduction of dopamine release; (5) significant increase in GABA release; (6) significant decrease in the number of monoaminergic presynaptic vesicles; (7) significant increase of dopamine concentration inside of monoaminergic vesicles; (8) significant increase of damaged mitochondria; (9) significant decrease of ATP level in the striatum (10) significant decrease in basal and maximal mitochondrial respiration. These results suggest that aminochrome induces dysfunction of dopaminergic neurons where the contralateral behavior can be explained by aminochrome-induced ATP decrease required both for anterograde transport of synaptic vesicles and dopamine release. Aminochrome could be implemented as a new model neurotoxin to study Parkinson's disease.
authors.affiliation: Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.|Department of Translational Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Herrera
authors.affiliation: Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Patricia
authors.initials: P
authors.lastname: Muñoz
authors.affiliation: Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.|Departamento de Ciencias Básicas, Universidad Santo Tomas, Viña del Mar, Chile.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Paris
authors.affiliation: Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Díaz-Veliz
authors.affiliation: Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mora
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jose
authors.initials: J
authors.lastname: Inzunza
authors.affiliation: Division of Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.affiliation: Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, University of Chile, Geroscience Center for Brain Health and Metabolism, , Santiago, Chile.
authors.forename: Cesar
authors.initials: C
authors.lastname: Cardenas
authors.affiliation: Anatomy and Developmental Biology Program, Institute of Biomedical Sciences, University of Chile, Geroscience Center for Brain Health and Metabolism, , Santiago, Chile.
authors.forename: Fabián
authors.initials: F
authors.lastname: Jaña
authors.affiliation: INSERM U1127, Paris, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
authors.affiliation: Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago, Chile.
authors.forename: Katia
authors.initials: K
authors.lastname: Gysling
authors.affiliation: Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago, Chile.
authors.forename: Jorge
authors.initials: J
authors.lastname: Abarca
authors.affiliation: Department of Translational Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile. jsegura@med.uchile.cl.
authors.forename: Juan
authors.identifier: 0000-0002-1018-673X
authors.initials: J
authors.lastname: Segura-Aguilar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D045563:Indolequinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology* / Q000662:veterinary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000032:analysis
chemical_list: D045563:Indolequinones; C091584:aminochrome 1; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Dopamine, neurodegeneration; Drugs; Mitochondria; Preclinical model; Presynaptic vesicles