Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington's disease

Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD.
Journal of Neurochemistry (Impact Factor: 4.28). 02/2013; 125(3). DOI: 10.1111/jnc.12190
Source: PubMed


Huntington's disease (HD) is a devastating genetic neurodegenerative disease caused by CAG trinucleotide expansion in the exon-1 region of the huntingtin gene. Currently, no cure is available. It is becoming increasingly apparent that mutant HTT impairs metabolic homeostasis and causes transcriptional dysregulation. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a transcriptional factor that plays a key role in regulating genes involved in energy metabolism; recent studies demonstrated that PPAR-γ activation prevented mitochondrial depolarization in cells expressing mutant HTT and attenuated neurodegeneration in various models of neurodegenerative diseases. PPAR-γ-coactivator 1α (PGC-1 α) transcription activity is also impaired by mutant HTT. We now report that the PPAR-γ agonist, rosiglitazone (RSG), significantly attenuated mutant HTT-induced toxicity in striatal cells and that the protective effect of RSG is mediated by activation of PPAR-γ. Moreover, chronic administration of RSG (10 mg/kg/d, i.p) significantly improved motor function and attenuated hyperglycemia in N171-82Q HD mice. RSG administration rescued BDNF deficiency in the cerebral cortex, and prevented loss of orexin-A-immunopositive neurons in the hypothalamus of N171-82Q HD mice. RSG also prevented PGC-1α reduction and increased Sirt6 protein levels in HD mouse brain. Our results suggest that modifying the PPAR-γ pathway plays a beneficial role in rescuing motor function as well as glucose metabolic abnormalities in HD. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12190.

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    • "Administration of a pan-PPAR agonist resulted in elevation of PCG-1α levels, amelioration of behavioral deficits, and increased survival (Johri et al., 2012). A recent study using a different HD model found that rosiglitazone prevented neuronal loss, improved mitochondrial function and restored PGC-1α levels in the brain (Jin et al., 2013). These studies have led to the conclusion that PGC-1α deficiency underlies the mitochondrial dysfunction observed in HD (Johri et al., 2013). "
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    • "PPARs are a group of nuclear receptor transducer proteins that functions as ligand-regulated transcription factors regulating the expression of genes [12]. Neuroprotective effects of PPARs have been described in various neurodegenerative disorders like Alzheimer's disease [13], stroke [14], Huntington's disease [15], and multiple sclerosis [16]. PPAR agonists have also shown to be effective in several in vitro and in vivo models of PD. "
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    ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disorder affecting 1% of the population by the age of 65 years and 4-5% of the population by the age of 85 years. PD affects functional capabilities of the patient by producing motor symptoms and nonmotor symptoms. Apart from this, it is also associated with a higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of fenofibrate, a PPAR- α agonist in cognitive impairment model in PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 µg/1 µL/side) produced significant cognitive dysfunctions. Fenofibrate treatment at 10, 30, and 100 mg/kg for twenty-five days was found to be neuroprotective and improved cognitive impairment in MPTP-induced PD model as evident from behavioral, biochemical (MDA, GSH, TNF- α , and IL-6), immunohistochemistry (TH), and DNA fragmentation (TUNEL positive cells) studies. Further, physiologically based pharmacokinetic (PBPK) modeling study was performed using GastroPlus to characterize the kinetics of fenofibric acid in the brain. A good agreement was found between pharmacokinetic parameters obtained from the actual and simulated plasma concentration-time profiles of fenofibric acid. Results of this study suggest that PPAR- α agonist (fenofibrate) is neuroprotective in PD-induced cognitive impairment.
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    • "In contrast, we found that the administration of RSG significantly rescued HFD-induced BDNF deficiency in the hippocampus. This result was consistent with findings from a previous study in which RSG administration rescued BDNF deficiency in the cerebral cortex of a model of Huntington's disease [16]. In addition, we previously observed that blocking the BDNF receptor reduces cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus of mice [38]. "
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    ABSTRACT: This study investigated how rosiglitazone (RSG) differentially affected on the hippocampal neurogenesis in low-fat diet (LFD)- and high-fat diet (HFD)-fed mice. LFD and HFD (60% fat) foods were provided to mice for 8 weeks. Starting from the 4 weeks after LFD and HFD feeding, vehicle or RSG was administered orally once a day to both groups of mice. We measured cell proliferation and neuroblast differentiation in the subgranular zone of the dentate gyrus using Ki67 and doublecortin (DCX), respectively. In addition, we determined the effects of RSG on the level of DCX and brain-derived neurotrophic factor (BDNF) in hippocampal homogenates. The number of Ki67- and DCX-positive cells and the hippocampal levels of DCX, and BDNF levels were significantly decreased in the RSG-treated group compared to the vehicle-treated group. In contrast, the number of Ki67- and DCX-positive cells and hippocampal levels of DCX, and BDNF were significantly increased in the RSG-treated group compared to the vehicle-treated group. RSG can modulate the levels of BDNF, which could play a pivotal role in cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus; the direction of this modulation depends on the condition of the central nervous system.
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