Funded Studies
Objective/Rationale:
Parkinson’s disease is characterized by the progressive loss of dopamine neurons in brain regions responsible for motor coordination and activity – disturbances of which are hallmark features of the disease. This neurodegeneration is linked to mitochondrial dysfunction, oxidative stress and the formation of reactive oxygen species (ROS), which are all thought to result, at least in part, from diminished glutathione levels. Cystine-glutamate exchange (system xc-) is a key regulator in the direct exchange of extracellular cystine for intracellular glutamate and provides cells with supplies of cystine used in the synthesis of the potent antioxidant, glutathione. Therefore, drugs designed to target system xc- should reduce oxidative stress and elicit neuroprotection via elevated levels of glutathione.
Project Description:
We have previously confirmed that our lead small molecules selectively target system xc- and effectively drive the exchange of cystine-glutamate in recombinant cell systems. We have also demonstrated that these molecules are effective in a variety of behavioral assays of neuropsychiatric disorders. In the present proposal, we seek to extend these pre-clinical findings by characterizing our advanced candidates in a disease-relevant model of Parkinson’s disease. Initially, we propose to characterize the pharmacokinetic (PK) profile of our compounds with an eye towards evaluating our most advanced lead molecule in the pre-clinical MPTP model of Parkinson’s disease.
Anticipated Outcome & Relevance to the Treatment of Parkinson’s disease:
We anticipate confirming our hypothesis that medications designed to target system xc- will have therapeutic value as neuroprotective agents in a model of Parkinson’s disease. Demonstration of this preclinical proof-of-efficacy that our lead molecule ameliorates symptoms in these studies will confirm that targeting system xc- exhibits the potential to slow or halt the progression of Parkinson’s disease.
Final Outcome
Building off data implicating oxidative stress-based mechanisms in the etiology of Parkinson’s we proposed that drugs designed to increase the activity of cysteine-glutamate exchange (system xc-), a unique protein in the brain regulating levels of glutamate and thiols (e.g., glutathione), will exert a therapeutic benefit in models of Parkinson's disease. Initially, we successfully demonstrated that our advanced molecules, as well engaging system xc- in general, do not produce excitotoxicity in cell culture. Next, we demonstrated that proprietary Promentis drugs have a favorable pharmacokinetic profile relative to N-acetyl cysteine, suggesting that these novel drugs are stable in plasma and readily enter the brain. Finally, we assessed the effects of two advanced molecules in the MPTP model of Parkinson's disease. In a series of experiments conducted by the laboratory of Dr. Michael Zigmond at the University of Pittsburgh, we found that MPTP produced a significant decrease in striatal dopamine levels; however, this manipulation was incomplete in that we did not obtain the anticipated alterations in behavior or in tissue levels of relevant thiols (as measured by levels of glutathione). Likely as a result of a lack of reduced levels of glutathione – a potentially important event in Parkinson’s, our compounds were ineffective in protecting against MPTP-induced lowering of dopamine.
Since the completion of these studies, Promentis has been exploring additional experiments to confirm assay conditions were a reduction in thiols can be observed. Initial studies done in cell culture suggest that there are possible differences in neuroprotection of related drugs (e.g., N-acetylcysteine) using the neurotoxin 6-OHDA (compared to MPP+). Future studies would focus on these differences and the potential therapeutic utility of our advanced small molecules in the 6-OHDA model of Parkinson's disease or in the evaluation of proprietary Promentis compound that receive IND status enabling us to test in humans.