Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson's disease

Introduction: Current treatment of Parkinson's disease (PD) is limited to symptomatic dopaminergic therapy, while no interventions have been shown to slow down disease progression. Areas covered: The following article highlights a group of PPAR-gamma agonists called thiazolidinediones (TZDs), which are currently being tested for a putative disease-modifying benefit in PD, using pioglitazone as a prototypic compound. PPAR-gamma is highly expressed in neurons of the substantia nigra and CNS immune cells. Preclinical data in rodent and primate support an effect of TZDs in preventing and/or arresting neurodegeneration and development of motor symptoms. Although no data on the neuroprotective effect of TZDs is currently available, a clinical trial is ongoing where the primary objective is to assess pioglitazone's impact on the progression of PD. The trial is also evaluating the drug's safety concerns. Expert opinion: The efficacy data from clinical trials must be carefully weighed against the safety concerns. However, given the solid preclinical data, and since the safety data are not yet fully conclusive and limited to the diabetic population, PPAR-gamma research in PD can continue with caution. Ideally, drug discovery and development efforts will lead to the identification of new compounds with reduced risk of peripheral side effects.