Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson's disease

Andrea Herrera, Patricia Munoz, Irmgard Paris, Gabriela Diaz-Veliz, Sergio Mora, Jose Inzunza, Kjell Hultenby, Cesar Cardenas, Fabian Jana, Rita Raisman-Vozari, Katia Gysling, Jorge Abarca, Harry W. M. Steinbusch, Juan Segura-Aguilar*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)3583-3597
JournalCellular and Molecular Life Sciences
Volume73
Issue number18
DOIs
Publication statusPublished - Sept 2016

Keywords

  • Preclinical model
  • Dopamine, neurodegeneration
  • Drugs
  • Mitochondria
  • Presynaptic vesicles

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