Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington's disease mice

Stack, Edward C.; Smith, Karen; Ryu, Hoon; Cormier, Kerry; Chen, Minghua; Hagerty, Sean W.; Signore, Steven J. Del; Cudkowicz, Merit; Friedlander, Robert M.; Ferrante, Robert J.

doi:10.1016/j.bbadis.2005.11.002

Cited by 111 publications

(77 citation statements)

References 33 publications

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“…By using this fundamentally restorative strategy in parallel with independent neuroprotective approaches, such as minocycline inhibition of caspase activity (53), histone deacetylase inhibitor support of neuronal transcription (24), Coenzyme Q and creatine support of neuronal energy reserves (39,(54)(55)(56), and FGF2 infusion (57), we might reasonably hope to establish a protocol for combination therapy of HD in affected individuals. In this regard, the 17% net increase in R6/2 survival that we observed following a single intraventricular injection of AdBDNF/AdNoggin is as robust an effect as any previously noted using any of these alternative neuroprotective strategies, alone or in combination.…”

Section: Discussionmentioning

confidence: 99%

Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease

et al. 2007

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Ependymal overexpression of brain-derived neurotrophic factor (BDNF) stimulates neuronal addition to the adult striatum, from subependymal progenitor cells. Noggin, by suppressing subependymal gliogenesis and increasing progenitor availability, potentiates this process. We asked whether BDNF/Noggin overexpression might be used to recruit new striatal neurons in R6/2 huntingtin transgenic mice. R6/2 mice injected with adenoviral BDNF and adenoviral Noggin (AdBDNF/AdNoggin) recruited BrdU + βIII-tubulin + neurons, which developed as DARPP-32 + and GABAergic medium spiny neurons that expressed either enkephalin or substance P and extended fibers to the globus pallidus. Only AdBDNF/AdNoggin-treated R6/2 mice harbored migrating doublecortin-defined neuroblasts in their striata, and the new neurons expressed p27 as a marker of mitotic quiescence after parenchymal integration. AdBDNF/AdNoggin-treated R6/2 mice sustained their rotarod performance and open-field activity and survived longer than did AdNull-treated and untreated controls. Neither motor performance nor survival improved in R6/2 mice treated only with AdBDNF, and intraventricular infusion of the mitotic inhibitor Ara-C completely blocked the performance and survival effects of AdBDNF/AdNoggin, suggesting that the benefits of AdBDNF/AdNoggin derived from neuronal addition. Thus, BDNF and Noggin induced striatal neuronal regeneration, delayed motor impairment, and extended survival in R6/2 mice, suggesting a new therapeutic strategy in Huntington disease.

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Section: Discussionmentioning

confidence: 99%

Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease

et al. 2007

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“…Agents that boost mitochondrial efficiency (e.g. creatine, coenzyme Q) are under investigation as potential therapeutic strategies in HD patients (Koroshetz et al, 1997;Matthews et al, 1998;Ferrante et al, 2000Ferrante et al, 2001Andreassen et al, 2001b;Schilling et al, 2001;Ferrante et al, 2002;Dedeoglu et al, 2003;Tabrizi et al, 2003;Verbessem et al, 2003;Ryu et al, 2005;Tabrizi et al, 2005;Hersch et al, 2006;Smith et al, 2006;Stack et al, 2006). While these studies strongly suggest that metabolic dysfunction may contribute to mutant huntingtin-mediated cell death, they fail to explain why the ubiquitous expression of mutant huntingtin has cytotoxic effects primarily in neurons (i.e.…”

Section: Introductionmentioning

confidence: 98%

Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease

Mihm

Amann

Schanbacher

et al. 2007

Neurobiology of Disease

126

116

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Recent evidence suggests that mutant huntingtin protein-induced energetic perturbations contribute to neuronal dysfunction in Huntington's disease (HD). Given the ubiquitous expression of huntingtin, other cell types with high energetic burden may be at risk for HD-related dysfunction. Early-onset cardiovascular disease is the second leading cause of death in HD patients; a direct role for mutant huntingtin in this phenomenon remains unevaluated. Here we tested the hypothesis that expression of mutant huntingtin is sufficient to induce cardiac dysfunction, using a well-described transgenic model of HD (line R6/2). R6/2 mice developed cardiac dysfunction by 8 weeks of age, progressing to severe failure at 12 weeks, assessed by echocardiography. Limited evidence of cardiac remodeling (e.g. hypertrophy, fibrosis, apoptosis, β 1 adrenergic receptor downregulation) was observed. Immunogold electron microscopy demonstrated significant elevations in nuclear and mitochondrial polyglutamine presence in the R6/2 myocyte. Significant alterations in mitochondrial ultrastructure were seen, consistent with metabolic stress. Increased cardiac lysine acetylation and protein nitration were observed, and were each significantly associated with impairments in cardiac performance. These data demonstrate that mutant huntingtin expression has potent cardiotoxic effects; cardiac failure may be a significant complication of this important experimental model of HD. Investigation of the potential cardiotropic effects of mutant huntingtin in humans may be warranted.

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“…HD is associated with up-regulated transglutaminase activity in selectively vulnerable brain regions and transglutaminase-catalyzed cross-links co-localize with hunttingtin (htt) protein aggregates [49]. Combination therapy using minocycline and coenzyme Q 10 (CoQ 10 ) in R6/2 transgenic HD mouse model also provided benefit by acting synergistically (minocycline attenuated microglia proliferation and CoQ 10 reduced htt protein aggregation) [50].…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

Role Of Lipids In Brain Injury And Diseases

2007

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SummaryLipid metabolism is of particular interest due to its high concentration in CNS. The importance of lipids in cell signaling and tissue physiology is demonstrated by many CNS disorders and injuries that involve deregulated metabolism. The long suffering lipid field is gaining reputation and respect as evidenced through the Center of Biomedical Research Excellence in Lipidomics and Pathobiology (COBRE), Lipid MAPS (Metabolites And Pathways Strategy) Consortium sponsored by NIH, European initiatives for decoding the lipids through genomic approaches, and Genomics of Lipidassociated Disorder (GOLD) project initiated by Austrian government. This review attempts to provide an overview of the lipid imbalances associated with neurological disorders (Alzheimer's, Parkinson's; Niemann-Pick; Multiple sclerosis, Huntington, amyotrophic lateral sclerosis, schizophrenia, bipolar disorders and epilepsy) and CNS injury (Stroke, traumatic brain injury; and spinal cord injury) and a few provocative thoughts. Lipidomic analyses along with RNA silencing will provide new insights into the role of lipid intermediates in cell signaling and hopefully open new avenues for prevention or treatment options. KeywordsAlzheimer's disease; Arachidonic acid; CDP-choline; CNS injury; Docosahexaenoic acid; Huntington disease; Lipid peroxidation; Neurodegenerative diseases; Phospholipases; Phospholipids; Stroke Lipids and the Central Nervous System (CNS)Phospholipids are important components of all mammalian cells and have a variety of biological functions: 1) formation of lipid bilayers that provide structural integrity necessary for protein function 2) function as an energy reservoir (for example triglycerides) and 3) serve as precursors for various second messengers such as arachidonic acid (ArAc), docosahexaenoic acid (DHA), ceramide, 1,2-diacylglycerol (DAG), phosphatidic acid, and lyso-phosphatidic acid. Lipids comprise a large number of chemically distinct molecules arising from combinations of fatty acids with various backbone structures. Overall, mammalian cells may contain ~1000-2000 lipid species [1]. Lipids are classified into eight categories (fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides) [2]. Subtypes of these eight lipid classes are given in Table 1 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript metabolism may be of particular importance for the CNS, as this organ has a high concentration of lipids, second only to adipose tissue.Neurodegenerative diseases, mental disorders, stroke and CNS traumas are problems of vast clinical importance. Currently there exists no cure for these CNS injuries and disorders, resulting in a huge impact on quality of life and an economic burden on society (Table 2, based on the US population statistics). The crucial role of lipids in tissue physiology and cell signaling is demonstrated by the many neurological disorders, including bipolar disorders and schizophrenia, and neurodegenerative ...

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Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington's disease mice

Cited by 111 publications

References 33 publications

Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease

Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease

Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease

Role Of Lipids In Brain Injury And Diseases

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