Abstract
The search for experimental models mimicking an early stage of Parkinson’s disease (PD) before motor manifestations is fundamental in order to explore early signs and get a better prognosis. Interestingly, our previous studies have indicated that 6-hydroxydopamine (6-OHDA) is a suitable model to induce an early degeneration of the nigrostriatal system without any gross motor impairment. Considering our previous findings, we aim to implement a novel system to monitor rats after intrastriatal injection of 6-OHDA to detect and analyze physiological changes underlying prodromal PD. Twenty male Sprague-Dawley rats were unilaterally injected with 6-OHDA (n = 10) or saline solution (n = 10) into the right striatum and placed in enriched environment cages where the activity was monitored. After 2 weeks, the amphetamine test was performed before the sacrifice. Immunohistochemistry was developed for the morphological evaluation and western blot analysis to assess molecular changes. Home-cage monitoring revealed behavioral changes in response to 6-OHDA administration including significant hyperactivity and hypoactivity during the light and dark phase, respectively, turning out in a change of the circadian timing. A preclinical stage of PD was functionally confirmed with the amphetamine test. Moreover, the loss of tyrosine hydroxylase expression was significantly correlated with the motor results, and 6-OHDA induced early proapoptotic events. Our findings provide evidence for a novel prodromal 6-OHDA model following a customized monitoring system that could give insights to detect non-motor deficits and molecular targets to test neuroprotective/neurorestorative agents.
Highlights
Parkinson’s disease (PD) is a complex neurologic disorder in which motor impairments occur, and other non-motor symptoms (NMS) play a relevant role, including hyposmia, sleep disorders, depression, constipation and cognitive deficit (Schapira and Tolosa, 2010; Mantri et al, 2018; Weintraub et al, 2018)
In the present study we aimed to detect prodromal changes in the behavior following an experimental model of PD based on the intrastriatal injection of 6-OHDA with a short time of evolution (2 weeks) in adult male rats housed in monitored enriched environment (EE) cages
6-OHDA-lesioned rats decreased significantly the number of activity areas during the dark phase, which is the active period of the rodent circadian cycle, comparing to Sham group (∗∗∗p < 0.0001, Mann-Whitney U-test) (Figure 2B)
Summary
Parkinson’s disease (PD) is a complex neurologic disorder in which motor impairments occur, and other non-motor symptoms (NMS) play a relevant role, including hyposmia, sleep disorders, depression, constipation and cognitive deficit (Schapira and Tolosa, 2010; Mantri et al, 2018; Weintraub et al, 2018). NMS may manifest several years prior to the onset of motor symptoms, even up to 20 years before the diagnosis, and the prevalence can vary between the patients (Schapira et al, 2017; Rees et al, 2019). In this context, there are not specific NMS for PD, the presence and combination of various NMS as well as the correlation with an early dopamine depletion may be useful for early diagnosis (Berg et al, 2013; Schapira et al, 2017). It is essential to establish a correlation between the early manifestations of PD (prodromal stage) with the clinical and pathological stage for an early diagnosis of PD (Mahlknecht et al, 2015; Liepelt-Scarfone et al, 2017; Sherbaf et al, 2018)
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