Protective effect of pioglitazone, a PPARγ ligand, in a 3 nitropropionic acid model of Huntington's disease

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the PPAR family. PPAR gamma is the target of insulin-sensitising thiazolidinediones (TZDs), drugs used for the treatment of non-insulin-dependent diabetes. Recently, several studies have shown that PPAR gamma activators can also prevent or attenuate neurodegeneration. The PPAR gamma agonist pioglitazone provides neuroprotection to dopaminergic neurons in lipopolysaccharide (LPS) and MPTP-induced Parkinson's disease experimental models. Here, we investigated whether PPAR gamma activation by pioglitazone protected striatal cells from mitochondrial dysfunction and oxidative stress in a 3 nitropropionic acid (3NP)-induced experimental model of Huntington's disease (HD). Our results suggested that pioglitazone has beneficial effects on mitochondrial dysfunction by interfering with the NF-kappa B signalling pathway, which has been implicated in the pathogenesis of HD. Additionally, we demonstrated that the nuclear translocation of HDAC3 is regulated by 3NP via I kappa B alpha and that treatment with pioglitazone prevented these effects. These results suggested that I kappa B alpha-dependent nuclear translocation is responsible for PPAR gamma inhibition by 3NP and pointed to histone modifications as a novel approach for treating HD. (C) 2011 Elsevier Inc. All rights reserved.