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  • 1
    Electronic Resource
    Electronic Resource
    Increased oxidative damage to DNA in a transgenic mouse model of Huntington's disease (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 79 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Huntington's disease (HD). We examined concentrations of 8-hydroxy-2-deoxyguanosine (OH8dG), a well-established marker of oxidative damage to DNA, in a transgenic mouse model of HD (R6/2). Increased concentrations of OH8dG were found in the urine, plasma and striatal microdialysates of the HD mice. Increased concentrations were also observed in isolated brain DNA at 12 and 14 weeks of age. Immunocytochemistry showed increased OH8dG staining in late stages of the illness. These results suggest that oxidative damage may play a role in the pathogenesis of neuronal degeneration in the R6/2 transgenic mouse model of HD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00689.x
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  • 2
    Electronic Resource
    Electronic Resource
    Mice Deficient in Group IV Cytosolic Phospholipase A2 Are Resistant to MPTP Neurotoxicity (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Phospholipase A2 (PLA2) enzymes are critical regulators of prostaglandin and leukotriene synthesis, and they may also play an important role in the generation of intracellular free radicals. The group IV cytosolic form of phospholipase A2 (cPLA2) is regulated by changes in intracellular calcium concentration, and the enzyme preferentially acts to release arachidonic acid esterified at the sn-2 position of phospholipids. We examined the susceptibility of mice carrying a targeted mutation of the cPLA2 gene to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Mutant mice have no functional cPLA2 activity. Mice that were homozygous for the mutation (cPLA2−/−) were significantly resistant to MPTP-induced dopamine depletion as compared with littermate control (cPLA2+/+) and heterozygous mice (cPLA2+/−). These findings provide evidence that cPLA2 plays a role in MPTP neurotoxicity and suggest that cPLA2 may play a role in the development of Parkinson's disease in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71062634.x
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  • 3
    Electronic Resource
    Electronic Resource
    Malonate and 3-Nitropropionic Acid Neurotoxicity Are Reduced in Transgenic Mice Expressing a Caspase-1 Dominant-Negative Mutant (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 75 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Increasing evidence implicates caspase-1-mediated cell death as a major mechanism of neuronal death in neurodegenerative diseases. In the present study we investigated the role of caspase-1 in neurotoxic experimental animal models of Huntington's disease (HD) by examining whether transgenic mice expressing a caspase-1 dominant-negative mutant are resistant to malonate and 3-nitropropionic acid (3-NP) neurotoxicity. Intrastriatal injection of malonate resulted in significantly smaller striatal lesions in mutant caspase-1 mice than those observed in littermate control mice. Caspase-1 was significantly activated following malonate intrastriatal administration in control mice but significantly attenuated in mutant caspase-1 mice. Systemic 3-NP treatment induced selective striatal lesions that were significantly smaller within mutant caspase-1 mice than in littermate control mice. These results provide further evidence of a functional role for caspase-1 in both malonate- and 3-NP-mediated neurotoxin models of HD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0750847.x
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  • 4
    Electronic Resource
    Electronic Resource
    Nonlinear Decrease over Time in N-Acetyl Aspartate Levels in the Absence of Neuronal Loss and Increases in Glutamine and Glucose in Transgenic Huntington's Disease Mice (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 74 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Mice transgenic for exon I of mutant huntingtin, with 141 CAG repeats, exhibit a profound symptomatology characterized by weight loss, motor disorders, and early death. We performed longitudinal analysis of metabolite levels in these mice using NMR spectroscopy in vivo and in vitro. These mice exhibited a large (53%), nonlinear drop in in vivo N-acetyl aspartate (NAA) levels over time, commencing at ∼6 weeks of age, coincident with onset of symptoms. These drops in NAA levels occurred in the absence of neuronal death as measured by postmortem Nissl staining and neuronal counting but in the presence of nuclear inclusion bodies. In addition to decreased NAA, these mice showed a large elevation of glucose in the brain (600%) consistent with a diabetic profile and elevations in blood glucose levels both before and after glucose loading. In vitro NMR analysis revealed significant increases in glutamine (100%), taurine (95%) cholines (200%), and scyllo-inositol (333%) and decreases in glutamate (24%) and succinate (47%). These results lead to two conclusions. NAA is reflective of the health of neurons and thus is a noninvasive marker, with a temporal progression similar to nuclear inclusion bodies and symptoms, of neuronal dysfunction in transgenic mice. Second, the presence of elevated glutamine is evidence of a profound metabolic defect. We present arguments that the elevated glutamine results from a decrease in neuronal-glial glutamate-glutamine cycling and a decrease in glutaminase activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0742108.x
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  • 5
    Electronic Resource
    Electronic Resource
    Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 77 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Several lines of evidence implicate excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis (ALS). Transgenic mice with a superoxide dismutase mutation (G93A) have been utilized as an animal model of familial ALS (FALS). We examined the cortical concentrations of glutamate using in vivo microdialysis and in vivo nuclear magnetic resonance (NMR) spectroscopy, and the effect of long-term creatine supplementation. NMDA-stimulated and ltrans-pyrrolidine-2,4-dicarboxylate (LTPD)-induced increases in glutamate were significantly higher in G93A mice compared with littermate wild-type mice at 115 days of age. At this age, the tissue concentrations of glutamate were also significantly increased as measured with NMR spectroscopy. Creatine significantly increased longevity and motor performance of the G93A mice, and significantly attenuated the increases in glutamate measured with spectroscopy at 75 days of age, but had no effect at 115 days of age. These results are consistent with impaired glutamate transport in G93A transgenic mice. The beneficial effect of creatine may be partially mediated by improved function of the glutamate transporter, which has a high demand for energy and is susceptible to oxidative stress.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00188.x
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  • 6
    Electronic Resource
    Electronic Resource
    Effects of CAG repeat length, HTT protein length and protein context on cerebral metabolism measured using magnetic resonance spectroscopy in transgenic mouse models of Huntington's disease (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 95 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Huntington's disease is a neurodegenerative illness caused by expansion of CAG repeats at the N-terminal end of the protein huntingtin. We examined longitudinal changes in brain metabolite levels using in vivo magnetic resonance spectroscopy in five different mouse models. There was a large (〉50%) exponential decrease in N-acetyl aspartate (NAA) with time in both striatum and cortex in mice with 150 CAG repeats (R6/2 strain). There was a linear decrease restricted to striatum in N171-82Q mice with 82 CAG repeats. Both the exponential and linear decreases of NAA were paralleled in time by decreases in neuronal area measured histologically. Yeast artificial chromosome transgenic mice with 72 CAG repeats, but low expression levels, had less striatal NAA loss than the N171–82Q mice (15% vs. 43%). We evaluated the effect of gene context in mice with an approximate 146 CAG repeat on the hypoxanthine phosphoribosyltransferase gene (HPRT). HPRT mice developed an obese phenotype in contrast to weight loss in the R6/2 and N171–82Q mice. These mice showed a small striatal NAA loss (21%), and a possible increase in brain lipids detectable by magnetic resonance (MR) spectroscopy and decreased brain water T1. Our results indicate profound metabolic defects that are strongly affected by CAG repeat length, as well as gene expression levels and protein context.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2005.03411.x
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  • 7
    Electronic Resource
    Electronic Resource
    Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis (1999)
    [s.l.] : Nature America Inc.
    Nature medicine 5 (1999), S. 347-350 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Mitochondria are particularly vulnerable to oxidative stress, and mitochondrial swelling and vacuolization are among the earliest pathologic features found in two strains of transgenic amyotrophic lateral sclerosis (ALS) mice with SOD1 mutations. Mice with the G93A human SOD1 mutation have altered ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/6568
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  • 8
    Electronic Resource
    Electronic Resource
    The relationship between motor effects in rats following acute and chronic haloperidol treatment (1994)
    Springer
    Psychopharmacology 116 (1994), S. 89-92 
    Details
    ISSN: 1432-2072
    Keywords: Animal models ; Haloperidol ; Vacous chewing movements ; Side-effects ; Acute administration ; Chronic administration ; Neuroleptics ; Tardive dyskinesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tardive dyskinesia (TD) is a serious and sometimes irreversible side-effect to long-term neuroleptic treatment. In order to find predictors for development of TD, it would be of interest to known whether susceptibility to develop acute side-effects increases the risk of TD development. The study investigated in female Sprague-Dawley rats the relationship between haloperidol-induced acute motor effects, assessed by means of the grid test and the open field test, and the chronic motor effect assessed as vacuous chewing movements (VCM). The doses of haloperidol were 1.2, 2.4 and 4.8 mg/kg IP in the acute experiments and haloperidol decanoate 38 mg/kg per 4 weeks IM in the chronic experiment. The VCM obtained at different timepoints during the 24 weeks of chronic treatment were highly correlated. However, no correlation was found between the motor effects in the acute and the chronic experiments. The study does not indicate any connection between susceptibility to acute side-effects on neuroleptics and later development of TD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02244876
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  • 9
    Electronic Resource
    Electronic Resource
    GM1 ganglioside attenuates the development of vacuous chewing movements induced by long-term haloperidol treatment of rats (1994)
    Springer
    Psychopharmacology 116 (1994), S. 517-522 
    Details
    ISSN: 1432-2072
    Keywords: Haloperidol ; Ganglioside GM1 ; Vacuous chewing movements ; Excitotoxicity ; Tardive dyskinesia ; Female rats ; Glutamate antagonism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if TD may be a result of neuroleptic-induced excessive stimulation of striatal glutamate receptors, the effect of the anti-excitotoxic GM1 ganglioside was studied in a rat model of TD. In an acute experiment each of four groups of rats was treated with GM1 20 mg/kg SC + saline IP, saline SC + haloperidol 1.2 mg/kg IP, GM1 SC + haloperidol IP, or saline SC + saline IP. In a subsequent long-term experiment lasting 16 weeks, each of the four groups was treated as in the acute experiment, with the exception that haloperidol was injected IM as decanoate 38 mg/kg every 4 weeks, and the controls received vehicle injections. The behaviour was videotaped and scored at intervals during both experiments, including 16 weeks after cessation of the long-term treatment. Haloperidol induced a significant increase in vacuous chewing movements (VCM) and immobility both in the acute and in the long-term experiment. Other categories of behaviour (rearing, moving, sitting) were significantly affected only in the acute experiment. GM1 did not affect any of the acute behavioural effects of haloperidol, but significantly reduced VCM in the long-term experiment. The effects on VCM of haloperidol and GM1 persisted for at least 8 weeks after cessation of the long-term treatment. These results suggest that long-lasting changes in striatal function induced by excessive glutamate receptor stimulation may be a mechanism for the development of VCM in rats and perhaps also for TD in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02247487
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  • 10
    Electronic Resource
    Electronic Resource
    Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients (1997)
    Springer
    Psychopharmacology 131 (1997), S. 174-179 
    Details
    ISSN: 1432-2072
    Keywords: Key words Anti-psychotic drugs ; Akathisia ; CYP2D6 genotype ; Parkinsonism ; Motor side-effects ; Poor metabolizer ; Schizophrenia ; Tardive dyskinesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The use of classic anti-psychotic drugs in the long-term treatment of schizophrenia is associated with risk for extrapyramidal side-effects, such as akathisia, parkinsonism and tardive dyskinesia (TD). Approximately 5–10% of European Caucasians lack the cytochrome P450 enzyme CYP2D6 (so-called poor metabolizers; PM), which normally metabolizes several drugs including many neuroleptics. PM subjects may achieve high or toxic plasma levels upon standard drug therapy. In this study we have examined 100 subjects from the Nithsdale cohort of schizophrenic patients in South-west Scotland receiving long-term neuroleptic medication, which enabled us to perform both a cross-sectional and longitudinal evaluation of extrapyramidal side-effects in relation to the genetically impaired CYP2D6 metabolism. We identified ten (10%) schizophrenic subjects with the PM genotype. In the cross-sectional study, the prevalence of TD, parkinsonism and akathisia was 51%, 38% and 15%, respectively. Patients with TD or parkinsonism were significantly older than patients without these side-effects. In contrast, patients with akathisia were significantly younger than patients without akathisia. There was a non-significant tendency for PM subjects to have more severe ratings for TD and parkinsonism. In the long-term evaluation based on repeated ratings since 1981, there was a non-significant 3-fold higher frequency of PM subjects among schizophrenic patients with longitudinal TD, as compared with the group of patients with fluctuating or no TD. These results indicate that genetically impaired CYP2D6 metabolism may be a contributing factor for the development of persistent TD.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050281
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