Abstract
The current treatments of Parkinson disease (PD) are ineffective mainly due to the poor understanding of the early events causing the decline of dopaminergic neurons (DOPAn). To overcome this problem, slow progressively degenerating models of PD allowing the study of the pre-clinical phase are crucial. We recreated in a short ex vivo time scale (96 h) all the features of human PD (needing dozens of years) by challenging organotypic culture of rat substantia nigra with low doses of rotenone. Thus, taking advantage of the existent knowledge, the model was used to perform a time-dependent comparative study of the principal possible causative molecular mechanisms undergoing DOPAn demise. Alteration in the redox state and inflammation started at 3 h, preceding the reduction in DOPAn number (pre-diagnosis phase). The number of DOPAn declined to levels compatible with diagnosis only at 12 h. The decline was accompanied by a persistent inflammation and redox imbalance. Significant microglia activation, apoptosis, a reduction in dopamine vesicle transporters, and the ubiquitination of misfolded protein clearance pathways were late (96 h, consequential) events. The work suggests inflammation and redox imbalance as simultaneous early mechanisms undergoing DOPAn sufferance, to be targeted for a causative treatment aimed to stop/delay PD.
Highlights
Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease [1]
The core pathologic feature of motor PD is the reduced production of the neurotransmitter dopamine in dopaminergic neurons (DOPAn) in the substantia nigra pars compacta (SN)
The results suggest that redox imbalance and inflammation are the early and simultaneous effectors of DOPAn demise
Summary
Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease [1]. The core pathologic feature of motor PD is the reduced production of the neurotransmitter dopamine in dopaminergic neurons (DOPAn) in the substantia nigra pars compacta (SN). The main consequence is the alteration of the nigrostriatal pathway, causing motor imbalance, associated to the recently acquired alterations of the other three dopaminergic pathways (the mesolimbic, the mesocortical and the tuberoinfundibular system) involved in the altered non-motor functions, constantly described in PD [2,3,4,5,6]. Nowadays is clear that PD is a multifactorial pathology. Several genes have been identified as risk-factors, but very few cases (about of 5–10%) are related to genetic mutations, and the majority of Parkinson cases are classified as sporadic [7,8]. Older age and male sex are a risk factor in developing PD [9]. Environmental factors, occupational exposure to heavy metals, as well specific pesticides are responsible for the pathogenesis [7]
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