Cerebral PET imaging and histological evidence of transglutaminase inhibitor cystamine induced neuroprotection in transgenic R6/2 mouse model of Huntington's disease

Wang, Xukui; Sarkar, Aparajita; Cicchetti, Francesca; Yu, Meixiang; Zhu, Aijun; Jokivarsi, Kimmo; Saint-Pierre, Martine; Brownell, Anna Liisa

doi:10.1016/j.jns.2004.12.011

Cited by 67 publications

(40 citation statements)

References 70 publications

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“…In patients and animals with HD, metabolic abnormalities and reductions in dopamine binding are well described in striatal and extrastriatal regions, progressively decreasing upon symptom severity [18,19,[41][42][43][44][45]. Here, [ 18 F]FDG values of the caudate-putamen were higher than, but positively correlated to D 2 impairment.…”

Section: Discussionmentioning

confidence: 83%

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

Casteels

Martı́nez

Bormans

et al. 2010

Eur J Nucl Med Mol Imaging

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Purpose Several lines of evidence imply early alterations in metabolic, dopaminergic and endocannabinoid neurotransmission in Huntington's disease (HD) receptor binding were reduced in the ipsilateral caudate-putamen by 7, 35 and 77%, respectively (all p<2.10 −5 ), while an increase for these markers was observed on the contralateral side (>5%, all p<7.10 −4 ).[ 18 F]MK-9470 binding was also increased in the cerebellum (p=2.10 −5 ), where it was inversely correlated to the number of ipsiversive turnings (p=7.10 −6 ), suggesting that CB 1 receptor upregulation in the cerebellum is related to a better functional outcome. Additionally, glucose metabolism was relatively increased in the contralateral hippocampus, thalamus and sensorimotor cortex (p=1.10 −6 ). Conclusion These data point to in vivo changes in endocannabinoid transmission, specifically for CB 1 receptors in the QA model, with involvement of the caudateputamen, but also distant regions of the motor circuitry, including the cerebellum. These data also indicate the occurrence of functional plasticity on metabolism, D 2 and CB 1 neurotransmission in the contralateral hemisphere.

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Section: Discussionmentioning

confidence: 83%

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

Casteels

Martı́nez

Bormans

et al. 2010

Eur J Nucl Med Mol Imaging

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“…Given these similarities to Parkinson's disease, our results support the possibility that cystamine administration could prevent or delay the onset of neurodegenerative diseases. Cystamine treatment was previously shown to be of benefit in murine models of Huntington's disease (Dedeoglu et al 2002;Karpuj et al 2002;Wang et al 2005) and Parkinson's disease (Sun et al 2010). Of note, cysteamine (as a bitartrate salt) has received Food and Drug Administration approval for treatment of a genetic disease (cystinosis) (Dohil et al 2010) and has recently been evaluated as a potential treatment for Huntington's disease (Borrell-Pages et al 2006) and for Parkinson's disease (Gibrat and Cicchetti 2011).…”

Section: Discussionmentioning

confidence: 99%

A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury

Zhang

Zheng

et al. 2016

Genetics

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Haloperidol is an effective antipsychotic agent, but it causes Parkinsonian-like extrapyramidal symptoms in the majority of treated subjects. To address this treatment-limiting toxicity, we analyzed a murine genetic model of haloperidol-induced toxicity (HIT). Analysis of a panel of consomic strains indicated that a genetic factor on chromosome 10 had a significant effect on susceptibility to HIT. We analyzed a whole-genome SNP database to identify allelic variants that were uniquely present on chromosome 10 in the strain that was previously shown to exhibit the highest level of susceptibility to HIT. This analysis implicated allelic variation within pantetheinase genes (Vnn1 and Vnn3), which we propose impaired the biosynthesis of cysteamine, could affect susceptibility to HIT. We demonstrate that administration of cystamine, which is rapidly metabolized to cysteamine, could completely prevent HIT in the murine model. Many of the haloperidol-induced gene expression changes in the striatum of the susceptible strain were reversed by cystamine coadministration. Since cystamine administration has previously been shown to have other neuroprotective actions, we investigated whether cystamine administration could have a broader neuroprotective effect. Cystamine administration caused a 23% reduction in infarct volume after experimentally induced cerebral ischemia. Characterization of this novel pharmacogenetic factor for HIT has identified a new approach for preventing the treatment-limiting toxicity of an antipsychotic agent, which could also be used to reduce the extent of brain damage after stroke. KEYWORDS pharmacogenetics; haloperidol toxicity H ALOPERIDOL is a potent D2 dopamine receptor (DRD2) antagonist that is used to treat psychotic disorders (Beresford and Ward 1987). However, haloperidol-induced alterations in the extrapyramidal motor system depress the ability to initiate voluntary movements. As a consequence, characteristic extrapyramidal symptoms (EPS), which include tremors, Parkinsonian rigidity, and decreased spontaneous movement, develop in 40-76% of human subjects that are chronically treated with haloperidol (Parkes 1982;Soares-Weiser and Fernandez 2007). We recently analyzed a murine genetic model of haloperidol-induced toxicity (HIT) (Zheng et al. 2015) in which the Parkinsonian-like symptoms developing in haloperidol-treated mice resemble those observed in drug-treated human patients (Crowley et al. 2012a). The 27 inbred strains evaluated in this genetic model exhibit substantial variability in susceptibility to HIT (Crowley et al. 2012b). For example, C57BL/6 mice are completely resistant, while A/J mice are highly susceptible to the Parkinsonian hypokinesia associated with HIT. We found that allelic differences in Abcb5, a member of the ABC-transporter gene family, affected susceptibility to this manifestation of HIT by regulating the level of haloperidol in the brain (Zheng et al. 2015). This pharmacogenetic effect is of importance, since haloperidol is oxidatively metabolized to a ...

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“…18 F]-FDG, demonstrated an exponential decrease in glucose metabolism, starting at the age of 8 weeks and continuing through the 6 weeks follow-up time in the striatum, cortex and cerebellum [ 88 ]. Treatment with the transglutaminase inhibitor cystamine in these animals has been shown to have a neuroprotective effect in a dose-dependent manner, attenuating the decrease in striatal, cortical and cerebellar […”

Section: Huntington's Diseasementioning

confidence: 99%

Applications of Small-Animal Imaging in Neurology and Psychiatry

Casteels

Habib

Laere

2014

Molecular Imaging of Small Animals

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Cerebral PET imaging and histological evidence of transglutaminase inhibitor cystamine induced neuroprotection in transgenic R6/2 mouse model of Huntington's disease

Cited by 67 publications

References 70 publications

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury

Applications of Small-Animal Imaging in Neurology and Psychiatry

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