Parkinson's disease is characterized by the progressive loss of specific cells of the brain region called substantia nigra that produce the chemical messenger dopamine. The current mainstay therapy is the administration of drugs that mimic dopamine action. Yet as the disease progresses they lose efficacy, and disabling side effects appear. A different strategy is the administration of therapies aimed to prevent neuronal cell death. Although several compounds have been proposed as neuroprotective agents, none has been ultimately proven successful in the clinic.
Pioglitazone is a drug currently used to treat people with diabetes, a disease in which blood levels of sugar are not well-regulated. Interestingly, pioglitazone has anti-inflammatory properties and the capacity to activate pathways, such as Nrf-2, that protect against oxidative stress. When chronically administered by mouth the drug is void of major side effects.
In pre-clinical models of PD, the oral administration of pioglitazone has been proven to prevent dopaminergic nigral cell loss. Based on these findings, our project analyzes the possibility of protecting dopaminergic cells in a non-human primate model of PD by oral administration of pioglitazone.
If this experiment is successful it may provide an innovative and simple alternative strategy to prevent the progression of the disease in PD patients. It will provide the proof-of-principle to develop a new class of compounds, for the treatment of PD and other neurodegenerative disorders. Furthermore, as pioglitazone is already approved for therapeutic use, proof of protection in a non-human primate model of PD will facilitate translation into clinical trials and to positively impact the health of PD patients.
Positive results will also bring awareness about the neuroprotective benefits of this anti-diabetic treatment. This is a relevant treatment issue considering that the hormonal disbalance found in diabetes may contribute to neurodegeneration and that diabetes and PD both increase their incidence with age and may develop in the same patients.
Final Outcome
The goal of this project was to examine whether pioglitazone, a selective PPARgamma antagonist that can cross the blood brain barrier, would be neuroprotective in a model of PD and whether it modulates the antioxidant response element (ARE). After overcoming formulation and dosing issues, the investigators successfully tested several doses of these compounds in MPTP models. Preliminary data suggested that the compounds were neuroprotective but did not modulate the antioxidant response element.
The researchers received supplemental funding to asess how much pioglitazone is in the cerebrospinal fluid after oral administration.