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

Abstract

The peroxisome proliferator-activated receptor γ (PPARγ) is a member of the PPAR family. PPARγ is the target of insulin-sensitising thiazolidinediones (TZDs), drugs used for the treatment of non-insulin-dependent diabetes. Recently, several studies have shown that PPARγ activators can also prevent or attenuate neurodegeneration. The PPARγ agonist pioglitazone provides neuroprotection to dopaminergic neurons in lipopolysaccharide (LPS) and MPTP-induced Parkinson's disease experimental models. Here, we investigated whether PPARγ 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-κB 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 IκBα and that treatment with pioglitazone prevented these effects. These results suggested that IκBα-dependent nuclear translocation is responsible for PPARγ inhibition by 3NP and pointed to histone modifications as a novel approach for treating HD.

• Authors: Maddalena Napolitano, Loredana Costa, Rocco Palermo, Alessandro Giovenco, Alessandra Vacca, Alberto Gulino
• Journal: Brain research bulletin (Brain Res Bull) Vol. 85 Issue 3-4 Pg. 231-7 (May 30 2011) ISSN: 1873-2747 [Electronic] United States
• PMID: 21440606 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• NF-kappa B
• Neuroprotective Agents
• Nitro Compounds
• Propionates
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• Thiazolidinediones
• Nitric Oxide Synthase Type I
• Nitric Oxide Synthase Type II
• Histone Deacetylases
• 3-nitropropionic acid
• Pioglitazone

Topics

• Analysis of Variance
• Animals
• Animals, Newborn
• Apoptosis (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Corpus Striatum (cytology)
• Gene Expression Regulation (drug effects)
• Histone Deacetylases (metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• NF-kappa B (genetics, metabolism)
• Neurons (drug effects)
• Neuroprotective Agents (pharmacology)
• Nitric Oxide Synthase Type I (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Nitro Compounds (toxicity)
• Pioglitazone
• Propionates (toxicity)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Thiazolidinediones (pharmacology)