"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). "
[Show abstract][Hide abstract] ABSTRACT: Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies.
Neurobiology of Disease 05/2014; 72. DOI:10.1016/j.nbd.2014.05.019 · 5.08 Impact Factor
"PPARs are a group of nuclear receptor transducer proteins that functions as ligand-regulated transcription factors regulating the expression of genes . Neuroprotective effects of PPARs have been described in various neurodegenerative disorders like Alzheimer's disease , stroke , Huntington's disease , and multiple sclerosis . PPAR agonists have also shown to be effective in several in vitro and in vivo models of PD. "
[Show abstract][Hide abstract] 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.
PPAR Research 02/2014; 2014(2):753587. DOI:10.1155/2014/753587 · 1.64 Impact Factor
"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 . In addition, we previously observed that blocking the BDNF receptor reduces cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus of mice . "
[Show abstract][Hide abstract] 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.
Sharen E McKay, Wayne Yan, Jessica Nouws, Maximilian J Thormann, Nuno Raimundo, Abdul Khan, Joseph Santos-Sacchi, Lei Song, Gerald S Shadel
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