Document Detail


Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington's disease.
MedLine Citation:
PMID:  23373812     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 Huntingtin (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/day, i.p) significantly improved motor function and attenuated hyperglycemia in N171-82Q HD mice. RSG administration rescued brain derived neurotrophic factor(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.
Authors:
Jing Jin; Jennifer Albertz; Zhihong Guo; Qi Peng; Gay Rudow; Juan C Troncoso; Christopher A Ross; Wenzhen Duan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-03-05
Journal Detail:
Title:  Journal of neurochemistry     Volume:  125     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-22     Completed Date:  2013-06-20     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  410-9     Citation Subset:  IM    
Copyright Information:
© 2013 International Society for Neurochemistry.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Anilides / pharmacology
Animals
Brain / drug effects,  enzymology,  pathology
Brain-Derived Neurotrophic Factor / metabolism
Cell Line
Disease Models, Animal
Gene Expression Regulation / drug effects,  genetics
Glutamates / genetics
Humans
Huntington Disease / complications,  drug therapy*,  genetics,  pathology
Hyperglycemia / drug therapy,  etiology
Intracellular Signaling Peptides and Proteins / metabolism
L-Lactate Dehydrogenase / metabolism
Male
Mice
Mice, Transgenic
Movement Disorders / drug therapy,  etiology
Nerve Tissue Proteins / genetics
Neurons / drug effects*,  metabolism
Neuropeptides / metabolism
Neuroprotective Agents / pharmacology,  therapeutic use*
PPAR gamma / antagonists & inhibitors
RNA, Messenger / metabolism
Sirtuins / metabolism
Thiazolidinediones / pharmacology,  therapeutic use*
Trans-Activators / genetics,  metabolism
Transcription Factors
Transfection
Trinucleotide Repeat Expansion / genetics
Grant Support
ID/Acronym/Agency:
NS072344/NS/NINDS NIH HHS; P30 DK079637/DK/NIDDK NIH HHS; R21 NS072344/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/2-chloro-5-nitrobenzanilide; 0/Anilides; 0/Brain-Derived Neurotrophic Factor; 0/Glutamates; 0/HTT protein, human; 0/Intracellular Signaling Peptides and Proteins; 0/Nerve Tissue Proteins; 0/Neuropeptides; 0/Neuroprotective Agents; 0/PPAR gamma; 0/Ppargc1a protein, mouse; 0/RNA, Messenger; 0/Thiazolidinediones; 0/Trans-Activators; 0/Transcription Factors; 0/orexins; 122320-73-4/rosiglitazone; 8L70Q75FXE/Adenosine Triphosphate; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 3.5.1.-/SIRT6 protein, human; EC 3.5.1.-/Sirtuins
Comments/Corrections

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