Changes in day/night activity in the 6-OHDA-induced experimental model of Parkinson´s disease: Exploring prodromal biomarkers

Abstract Background: Parkinson’s disease (PD) is a prevalent neurodegenerative disorder for which there is not currently a cure and when it is clinically diagnosed is likely too late. The search for experimental models mimicking an early stage of 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. Methods: Rats were unilaterally injected with 6-OHDA or saline solution into the striatum and placed in enriched environment cages where the activity was monitored. After two weeks, the amphetamine test was performed before the sacrifice. Immunohistochemistry was developed for the morphological evaluation and western blot analysis to assess molecular changes. Results: 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. Conclusions: 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.