Glutathione (GSH) is an antioxidant produced naturally by cells thereby providing them with a defense against oxidative stress. There is good evidence that GSH levels decrease in PD and may contribute to disease development. My laboratory has identified a neuroprotective and memory-enhancing small molecule called fisetin. At least part of the neuroprotective effect of fisetin is due to its ability to maintain GSH levels. Thus, we propose that fisetin or more potent derivatives could be useful for the treatment of PD.
We propose to use medicinal chemistry to create more potent fisetin derivatives, to characterize these derivatives and to test them in a pre-clinical model of PD. We will make modifications of fisetin in order to improve its potency and efficacy and test these derivatives in cell-based models of PD to determine if they have properties similar to fisetin, including the maintenance of GSH levels. The four best derivatives will be tested in a well-characterized pre-clinical model of PD. We have already found that fisetin is protective in this model and we would expect that at least one of the derivatives will be much more effective.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current PD drugs treat only the symptoms of the disease and none are able to prevent further nerve cell loss or address the cognitive problems that are associated with PD. Thus, a drug that is able to both slow the progression of the disease as well as treat one of its most debilitating symptoms would make a very significant contribution to the treatment of PD. We have identified a novel compound, fisetin, that is orally active, neuroprotective and enhances memory. Thus, fisetin or a derivative could provide a novel approach to the treatment of PD.
Our preliminary results indicate that fisetin is protective in a pre-clinical model of PD. By the completion of our studies, we expect to have a fisetin derivative that is more effective at a lower dose than fisetin in this PD model and that also has the other beneficial properties of fisetin including maintaining GSH levels.
Dr. Maher has synthesized and screened a number of derivatives of the compound fisetin in cell toxicity assays. However, studies in the MPTP rodent model have shown limited protection suggesting that these derivative compounds need to maintain multiple targets of action to be therapeutically useful.