Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington's disease

Stack, Cliona; Ho, Daniel J.; Wille, Elizabeth; Calingasan, Noel Y.; Williams, Charlotte R.; Liby, Karen T.; Sporn, Michael B.; Dumont, Magali; Beal, M. Flint

doi:10.1016/j.freeradbiomed.2010.03.017

Cited by 156 publications

(135 citation statements)

References 76 publications

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“…In this regard, activation of the NFE2L2 pathway has been reported as being beneficial at decreasing the behavioral abnormalities and brain pathology in a murine model of Huntington disease. 77 …”

Section: Figurementioning

confidence: 99%

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

Napoli¹,

Wong²,

Hertz‐Picciotto

et al. 2014

Pediatrics

103

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Despite the emerging role of mitochondria in immunity, a link between bioenergetics and the immune response in autism has not been explored. Mitochondrial outcomes and phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst were evaluated in granulocytes from age-, race-, and gender-matched children with autism with severity scores of $7 (n = 10) and in typically developing (TD) children (n = 10). The oxidative phosphorylation capacity of granulocytes was 3-fold lower in children with autism than in TD children, with multiple deficits encompassing $1 Complexes. Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children' s mean values) of the nuclear factor erythroid 2-related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network.

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Section: Figurementioning

confidence: 99%

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

Napoli¹,

Wong²,

Hertz‐Picciotto

et al. 2014

Pediatrics

103

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“…The recent identification of a phenotype in a "glial-only" polyQ-htt mouse calls attention to the fact that the NF-E2-related factor-2 (Nrf2)/antioxidant response element-mediated protective pathway is largely localized to astrocytes [117]. This pathway appears to protect neurons from oxidative stress in HD mouse models [118], highlighting the importance of mRNA cellular localization in all HD mouse models. Notably, there is an absence of alterations in most dopamine pathway-related genes in the D9-N171-98Q mouse.…”

Section: Transcriptional Dysregulationmentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

126

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Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

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“…CDDO-MA also improves spatial memory and reduces the number and size of amyloid plaques in the hippocampus in a model of Alzheimer's disease in which mice carry two mutations in the human amyloid precursor protein (Dumont et al, 2009). Compared with CDDO-MA, higher drug levels of CDDO-EA and CDDO-TFEA can be obtained in the brain, and both of these amides prolong survival in transgenic mouse models of Huntington's disease (Stack et al, 2010) and ALS (Neymotin et al, 2011). Even when treatment is delayed until the onset of motor symptoms in G93A SOD1 mice, the SOs slow progression of ALS and extend the lifespan of these mice (Neymotin et al, 2011).…”

mentioning

confidence: 99%

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

2012

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Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington's disease

Cited by 156 publications

References 76 publications

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

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