Article

D-β-Hydroxybutyrate Is Protective in Mouse Models of Huntington's Disease

Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, New York, United States of America.
PLoS ONE (Impact Factor: 3.53). 09/2011; 6(9):e24620. DOI: 10.1371/journal.pone.0024620
Source: PubMed

ABSTRACT Abnormalities in mitochondrial function and epigenetic regulation are thought to be instrumental in Huntington's disease (HD), a fatal genetic disorder caused by an expanded polyglutamine track in the protein huntingtin. Given the lack of effective therapies for HD, we sought to assess the neuroprotective properties of the mitochondrial energizing ketone body, D-β-hydroxybutyrate (DβHB), in the 3-nitropropionic acid (3-NP) toxic and the R6/2 genetic model of HD. In mice treated with 3-NP, a complex II inhibitor, infusion of DβHB attenuates motor deficits, striatal lesions, and microgliosis in this model of toxin induced-striatal neurodegeneration. In transgenic R6/2 mice, infusion of DβHB extends life span, attenuates motor deficits, and prevents striatal histone deacetylation. In PC12 cells with inducible expression of mutant huntingtin protein, we further demonstrate that DβHB prevents histone deacetylation via a mechanism independent of its mitochondrial effects and independent of histone deacetylase inhibition. These pre-clinical findings suggest that by simultaneously targeting the mitochondrial and the epigenetic abnormalities associated with mutant huntingtin, DβHB may be a valuable therapeutic agent for HD.

Download full-text

Full-text

Available from: David Blum, Jul 01, 2015
0 Followers
 · 
241 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mouse models of human diseases are created both to understand the pathogenesis of the disorders and to find successful therapies for them. This work is the second part in a series of reviews of mouse models of polyglutamine (polyQ) hereditary disorders and focuses on in vivo experimental therapeutic approaches. Like part I of the polyQ mouse model review, this work is supplemented with a table that contains data from experimental studies of therapeutic approaches in polyQ mouse models. The aim of this review was to characterize the benefits and outcomes of various therapeutic strategies in mouse models. We examine whether the therapeutic strategies are specific to a single disease or are applicable to more than one polyQ disorder in mouse models. In addition, we discuss the suitability of mouse models in therapeutic approaches. Although the majority of therapeutic studies were performed in mouse models of Huntington disease, similar strategies were also used in other disease models. Electronic supplementary material The online version of this article (doi:10.1007/s12035-012-8316-3) contains supplementary material, which is available to authorized users.
    Molecular Neurobiology 09/2012; 46(2):430-66. DOI:10.1007/s12035-012-8316-3 · 5.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress has an important role in neurodegenerative diseases and cerebral ischemic injury. It is reported that d-β-hydroxybutyrate (DβHB), the major component of ketone bodies, is neuroprotective in recent studies. Therefore, in the present work the neuroprotective effects of DβHB on H(2)O(2)-induced apoptosis mediated by oxidative stress was investigated. PC12 cells were exposed to H(2)O(2) with different concentrations of H(2)O(2) for different times after DβHB pretreatment. MTT assay, apoptotic rates, intracellular reactive oxygen species (ROS) level, GSH content, mitochondrial membrane potential (MMP) and caspase-3 activity were determined. The results showed that DβHB inhibited the decrease of cell viability induced by H(2)O(2) in PC12 cells. DβHB decreased the apoptotic rates induced by H(2)O(2). The changes of intracellular ROS, GSH, MMP and caspase-3 activity due to H(2)O(2) exposure were partially reversed in PC12 cells. So DβHB inhibited the apoptosis of PC12 cells induced by H(2)O(2) via inhibiting oxidative stress.
    Neurochemistry International 09/2012; 62(5). DOI:10.1016/j.neuint.2012.09.011 · 2.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Multiple Sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system (CNS) gray and white matter. Although the cause of MS is unknown, it is widely appreciated that innate and adaptive immune processes contribute to its pathogenesis. These include microglia/macrophage activation, pro-inflammatory T-cell (Th1) responses and humoral responses. Additionally, there is evidence indicating that MS has a neurodegenerative component since neuronal and axonal loss occurs even in the absence of overt inflammation. These aspects also form the rationale for clinical management of the disease. However, the currently available therapies to control the disease are only partially effective at best indicating that more effective therapeutic solutions are urgently needed. It is appreciated that in the immune-driven and neurodegenerative processes MS-specific deregulation of gene expressions and resulting protein dysfunction are thought to play a central role. These deviations in gene expression patterns contribute to the inflammatory response in the CNS, and to neuronal or axonal loss. Epigenetic mechanisms control transcription of most, if not all genes, in nucleated cells including cells of the CNS and in haematopoietic cells. MS-specific alterations in epigenetic regulation of gene expression may therefore lie at the heart of the deregulation of gene expression in MS. As such, epigenetic mechanisms most likely play an important role in disease pathogenesis. In this review we discuss a role for MS-specific deregulation of epigenetic features that control gene expression in the CNS and in the periphery. Furthermore, we discuss the application of small molecule inhibitors that target the epigenetic machinery to ameliorate disease in experimental animal models, indicating that such approaches may be applicable to MS patients.
    01/2013; 3(2). DOI:10.1016/j.msard.2013.08.007