Preclinical neuroprotective trials of a PPAR-gamma agonist in HD mouse models

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DESCRIPTION (provided by applicant): Huntington disease (HD) is a neurodegenerative disease that is caused by the pathological elongation of the CAG repeats in the huntingtin gene. There is no treatment to delay onset and/or slow down the progression of disease in humans. Transcriptional dysregulation and mitochondrial dysfunction have been strongly implicated in the pathogenesis of HD. Peroxisome proliferator- activated receptors (PPARs) are members of the nuclear hormone receptor family of ligand- activated transcription factors. PPAR? activation prevents neuronal degeneration with a concomitant increase in mitochondrial viability. Recent studies have also provided evidence that PPAR? agonists are neuroprotective and increase mitochondrial function in a cell model of HD. Our preliminary studies indicated that mutant huntingtin altered the PPAR? levels in both cell models and mouse model of HD, and PPAR? agonist rosiglitazone protected cells against mutant huntingtin-induced cell death in cell models and extended survival in a HD mouse model. Therefore, we propose to determine the possibility of PPAR? activation to ameliorate mutant huntingtin-induced pathology and dysfunction in vivo. In Aim 1, we will determine the dose response and effect of PPAR-gamma agonist rosiglitazone on disease onset and progression in a fragment mutant huntingtin transgenic mouse model (N171-82Q mice). We will chronically administer three doses of rosiglitazone (10, 20, 40 mg/kg/day, i.p) to N171-82Q HD mice. Drug injection will be started at 6 weeks of age for presymptomatic trials and at 12 weeks of age for symptomatic trials. Motor behavioral performance will be assessed by accelerating rotarod apparatus. Effect of rosiglitazone on brain atrophy will be examined longitudinally by using structural MRI at 6, 12 and 18 weeks of age for presymptomatic trials and at 16, 20 weeks for symptomatic trials. The onset of disease will be evaluated by first detectable rotarod deficit. Drug concentrations will be measured by HPLC/MS/MS. Effect of rosiglitazone on brain pathological change will be also evaluated by histological analysis. In Aim 2, we will determine the effect of rosiglitazone on motor function and brain pathology in a full-length mutant huntingtin transgenic mouse model (BACHD mice). We will chronically administer optimal dose of rosiglitazone to BACHD mice before onset and after onset of motor deficit. Motor behavioral performance will be assessed by rotarod apparatus. Brain atrophy will be examined by using MRI at 6 and 12 months of age and neuropathology will be examined by histology at 12 months. The proposed study will provide critical evidence for further clinical trials of PPAR? agonists in humans. Our long-term goal is to develop effective therapeutic agents for HD patients. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is the most common inherited disorder affecting the nervous system in humans and shares many features with other neurodegenerative diseases. There is no cure, nor are there effective treatments that delay the onset or slow down the progression of HD. Our proposed studies will examine the effect of a clinical approved PPAR? agonist on disease onset and progression in mouse models of HD and result in a strategy to develop therapeutics for HD.