Neuroprotective effects of peroxisome proliferator-activated receptor-gamma (PPAR-y) ligands against oxidative stress

Aoun, Paul Neuroprotective effects of peroxisome proliferator-activated receptor-gamma (PPAR-y) ligands against oxidative stress. Doctor of Philosophy (Pharmacology and Neurosciences), December, 2003, 254 pp., 37 figures. Diabetes mellitus is a significant public health problem in the United States and the world resulting in substantial morbidity and mortality. Diabetes complications, i.e., neuropathy, are common and almost triple the annual cost of managing diabetes. In our studies, we investigated the role that insulin sensitizers currently used for the treatment of diabetes, the PPAR-y ligands, might play in protecting neurons against oxidative stresses. We showed that two PPAR-y ligands, 15 deoxy-PGJ2 and troglitazone, protected, in a dose-dependent manner, HT-22 mouse hippocampal and RGC-5 retinal ganglion cell lines against various oxidative insults. Further, we demonstrated that neuroprotection by 15deoxy-PGJ2 and troglitazone was independent of the PPAR-y receptor. Our findings brought to light an important role of PPAR-y ligands in preventing neuronal complications from diabetes. Moreover, the studies reported herein provide valuable insights into the development of novel therapeutic compounds that improve insulin sensitivity while preventing neurological, and possibly other complications of diabetes.