Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington's disease.
ABSTRACT 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.
Article: The role of SIRT1 in ocular aging[Show abstract] [Hide abstract]
ABSTRACT: The sirtuins are a highly conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases that helps regulate the lifespan of diverse organisms. The human genome encodes seven different sirtuins (SIRT1-7), which share a common catalytic core domain but possess distinct N- and C-terminal extensions. Dysfunction of some sirtuins have been associated with age-related diseases, such as cancer, type II diabetes, obesity-associated metabolic diseases, neurodegeneration, and cardiac aging, as well as the response to environmental stress. SIRT1 is one of the targets of resveratrol, a polyphenolic SIRT1 activator that has been shown to increase the lifespan and to protect various organs against aging. A number of animal studies have been conducted to examine the role of sirtuins in ocular aging. Here we review current knowledge about SIRT1 and ocular aging. The available data indicate that SIRT1 is localized in the nucleus and cytoplasm of cells forming all normal ocular structures, including the cornea, lens, iris, ciliary body, and retina. Upregulation of SIRT1 has been shown to have an important protective effect against various ocular diseases, such as cataract, retinal degeneration, optic neuritis, and uveitis, in animal models. These results suggest that SIRT1 may provide protection against diseases related to oxidative stress-induced ocular damage, including cataract, age-related macular degeneration, and optic nerve degeneration in glaucoma patients.Experimental Eye Research 07/2013; 116. DOI:10.1016/j.exer.2013.07.017 · 3.02 Impact Factor
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ABSTRACT: The oxidative phosphorylation (OXPHOS) system in mitochondria is responsible for the generation of the majority of cellular energy in the form of ATP. Patients with genetic OXPHOS disorders form the largest group of inborn errors of metabolism. Unfortunately, there is still a lack of efficient therapies for these disorders other than management of symptoms. Developing therapies has been complicated because, although the total group of OXPHOS patients is relatively large, there is enormous clinical and genetic heterogeneity within this patient population. Thus there has been a lot of interest in generating relevant mouse models for the different kinds of OXPHOS disorders. The most common treatment strategies tested in these mouse models have aimed to upregulate mitochondrial biogenesis, with the rationale of increasing the residual OXPHOS activity present in affected animals and thereby ameliorating the energy deficiency. Drugs such as bezafibrate, resveratrol and AICAR target the master regulator of mitochondrial biogenesis PGC-1α either directly or indirectly to manipulate mitochondrial metabolism. This review will summarize the outcome of pre-clinical treatment trials with these drugs in mouse models of OXPHOS disorders and discuss similar treatments in a number of mouse models of common diseases in which pathology is closely linked to mitochondrial dysfunction. In the majority of these studies the pharmacological activation of the PGC-1α axis shows true potential as therapy, however other effects besides mitochondrial biogenesis may be contributing to this as well.British Journal of Pharmacology 09/2013; DOI:10.1111/bph.12413 · 4.99 Impact Factor
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ABSTRACT: A study was conducted to assess the physiopathological significance of sirtuin 6 (SIRT6) at the brain cortical level. We analyzed the specific expression and subcellular localization of SIRT6 in young db/db mice, an experimental animal model of type II Diabetes mellitus. We analyzed the cytoarchitecture of the brain cortex, evaluated SIRT6 expression and its localization by immunohistochemistry comparing db/db mice to lean control mice, examining the six cortical layers and the motor and somatosensory cortex. Finally, we calculated a SIRT6 labeling index. We observed the absence of significant morphological differences between lean and db/db mice, indicating that young db/db mice showed a neuronal morphology and distribution similar to that of lean mice and also normal brain tissue architecture with intact cortical layers. Moreover, sirtuin 6 is mainly localized in the nucleus of both lean and db/db mice. In particular, the db/db mice showed few positive cells compared to lean control mice in all cortical layers. We found a lower sirtuin 6 labeling index without significant differences between the motor and somatosensory cortex. Our findings contribute to further understanding the sirtuin 6 immunohistochemical changes in the early stages of type II Diabetes mellitus and propose its possible implication in the pathogenic processes associated with Diabetes mellitus and diabetes-induced neurodegeneration.Acta histochemica 09/2013; DOI:10.1016/j.acthis.2013.08.006 · 1.76 Impact Factor