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Date of Award
As part of our long-term objective and continued efforts in developing an efficient multifunctional therapy for PD, this thesis is one such endeavors and my aim was to study the effect of multifunctional dopamine agonist D-512 against Rotenone induced toxicity in PD model. The goal of our experiments was to demonstrate the effectiveness of D-512 in protecting neuronal cells against Rotenone toxicity.
To evaluate neuroprotective capability of D-512, we pretreated MN9D cells with D-512 followed by co-treatment with Rotenone. Substantial increase in cell viability was observed. Mitochondrial dysfunction and subsequent increase in reactive oxygen species is one of the reasons for death of dopamine cells which is one of the pathogenesis of PD.
In order to delineate the mechanisms involved in neuroprotective effects of D-512, one of the studies performed by us was to study the effect of D-512 on restoring Mitochondrial Membrane Potential. In both MN9D and PC-12 cells, D-512 showed restoration of Mitochondrial membrane potential which was lost due to rotenone treatment.
Oxidative stress has been shown to be one of the important causes of progression of PD. Neuroprotection corresponds with reduction in intracellular ROS. To establish the efficacy of D-512 in reducing ROS, we observed that PC12 cells pretreated with D-512 showed reduction of ROS which was increased due to treatment with Rotenone. In our experiment of time dependent Rotenone treatment proved that D-512 pretreatment was able to bring the levels of ERK in PC12 cells.
The loss of Tyrosine Hydroxylase levels was also found to be restored when compared to D-512 treatment proving the increase in the dopaminergic levels in the cells. These neuroprotective properties exhibited by D-512 strongly imply that it may be obvious choice of therapy for PD in future.
Ravipati, Pranay, "Mechanism Of A Multifunctional Dopamine Agonist Against Rotenone Induced Toxicity: Implication In Parkinson's Disease Therapy" (2017). Wayne State University Theses. 640.