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  • 1
    ISSN: 1432-1440
    Keywords: Key words Gαi2 ; Insulin action ; Hexose transport ; Transgenic mice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Deficiency of the G protein subunit Gαi2 that is known to mediate the inhibitory control of adenylylcyclase impairs insulin action [11]. Using the promoter for the phosphoenolpyruvate carboxykinase gene, conditional, tissue-specific expression of the constitutively active mutant form (Q205L) of Gαi2 was achieved in mice harboring the transgene. Expression of Q205L Gαi2 was detected in liver and adipose tissue of transgenic mice. Whereas the Gαi2 deficient mice displayed blunted glucose tolerance, the Q205L Gαi2 expressing mice displayed enhanced glucose tolerance. Hexose transport and the recruitment of GLUT4, but not GLUT1, transporters to the membrane were elevated in adipocytes from Q205L Gαi2 expressing mice in the absence of insulin. Additionally, hepatic glycogen synthase was found to be activated in Q205L Gαi2 expressing mice, in the absence of the administration of insulin. Serum insulin levels in transgenic mice fasted overnight were equivalent to those of their control littermates. These data demonstrate that much as Gαi2 deficiency leads to insulin resistance, expression of Q205L constitutively active Gαi2 mimics insulin action in vivo, reflecting a permissive role of Gαi2 in signaling via this growth factor receptor tyrosine kinase linked pathway.
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  • 2
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] Inactivation of the adenosine A2A receptor (A2AR) consistently protects against ischemic brain injury and other neural insults, but the relative contribution of A2ARs on peripheral inflammatory cells versus A2ARs expressed on neurons and glia is unknown. We created a chimeric mouse model in which ...
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Adenosine A2A receptor (A2AR) antagonism attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and quinolinic acid-induced excitotoxicity in the neostriatum. As A2ARs are enriched in striatum, we investigated the effect of genetic and pharmacological A2A inactivation on striatal damage produced by the mitochondrial complex II inhibitor 3-nitropriopionic acid (3-NP). 3-NP was administered to A2AR knockout (KO) and wild-type (WT) littermate mice over 5 days. Bilateral striatal lesions were analyzed from serial brain tissue sections. Whereas all of the 3-NP-treated WT mice (C57BL/6 genetic background) had bilateral striatal lesions, only one of eight of the 3-NP-treated A2AR KO mice had detectable striatal lesions. Similar attenuation of 3-NP-induced striatal damage was observed in A2AR KO mice in a 129-Steel background. In addition, the effect of pharmacological antagonism on 3-NP-induced striatal neurotoxicity was tested by pre-treatment of C57Bl/6 mice with the A2AR antagonist 8-(3-chlorostyryl) caffeine (CSC). Although bilateral striatal lesions were observed in all mice treated either with 3-NP alone or 3-NP plus vehicle, there were no demonstrable striatal lesions in mice treated with CSC (5 mg/kg) plus 3-NP and in five of six mice treated with CSC (20 mg/kg) plus 3-NP. We conclude that both genetic and pharmacological inactivation of the A2AR attenuates striatal neurotoxicity produced by 3-NP. Since the clinical and neuropathological features of 3-NP-induced striatal damage resemble those observed in Huntington's disease, the results suggest that A2AR antagonism may be a potential therapeutic strategy in Huntington's disease patients.
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  • 4
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The present study evaluated whether nuclear factor-κB (NF-κB) activation contributes to the apoptotic-like death of striatal neurons induced by kainic acid (KA) receptor stimulation. Intrastriatally infused KA (1.25-5.0 nmol) produced substantial neuronal loss as indicated by an 8-73% decrease in 67-kDa glutamic acid decarboxylase (p 〈 0.05). KA (1.25-5.0 nmol) elicited internucleosomal DNA fragmentation that was inhibited by the AMPA/KA receptor antagonist NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dibenzo[f]quinoxaline-7-sulfonamide) but not by the NMDA receptor antagonist MK-801. A decrease in IκB-α protein levels, which was accompanied by an increase in NF-κB binding activity, was found from 6 to 72 h after KA (2.5 nmol) infusion. NF-κB was composed mainly of p65 and c-Rel as revealed by supershift assay. In addition, c-Myc and p53 increased from five- to sevenfold from 24 to 72 h after KA (2.5 nmol) administration. Immunohistochemistry revealed high levels of c-Myc and p53 immunoreactivity, mainly in medium-sized striatal neurons. Pretreatment with the cell-permeable recombinant peptide NF-κB SN50 (5-20 μg) blocked NF-κB nuclear translocation, but had no effect on AP-1 binding. NF-κB SN50 also inhibited the KA-induced up-regulation of c-Myc and p53, as well as internucleosomal DNA fragmentation. The apoptotic-like destruction of rat striatal neurons induced by KA receptor stimulation thus appears to involve biochemical mechanisms similar to those mediating the excitotoxic response to NMDA receptor stimulation. The present results provide additional support for the view that NF-κB activation contributes to c-Myc and p53 induction and subsequent apoptosis in an excitotoxic model of Huntington’s disease.
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  • 5
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The absence of adenosine A2A receptors, or its pharmacological inhibition, has neuroprotective effects. Experimental data suggest that glial A2A receptors participate in neurodegeneration induced by A2A receptor stimulation. In this study we have investigated the effects of A2A receptor stimulation on control and activated glial cells. Mouse cortical mixed glial cultures (75% astrocytes, 25% microglia) were treated with the A2A receptor agonist CGS21680 alone or in combination with lipopolysaccharide (LPS). CGS21680 potentiated lipopolysaccharide-induced NO release and NO synthase-II expression in a time- and concentration-dependent manner. CGS21680 potentiation of lipopolysaccharide-induced NO release was suppressed by the A2A receptor antagonist ZM-241385 and did not occur on mixed glial cultures from A2A receptor-deficient mice. In mixed glial cultures treated with LPS + CGS21680, the NO synthase-II inhibitor 1400W abolished NO production, and NO synthase-II immunoreactivity was observed only in microglia. Binding experiments demonstrated the presence of A2A receptors on microglial but not on astroglial cultures. However, the presence of astrocytes was necessary for CGS21680 potentiating effect. In light of the reported neurotoxicity of microglial NO synthase-II and the neuroprotection of A2A receptor inhibition, these data suggest that attenuation of microglial NO production could contribute to the neuroprotection afforded by A2A receptor antagonists.
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  • 6
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: To study the effects of altering dopaminergic input on the levels and rate of synthesis of dopamine receptors, corpora striata of mice were lesioned unilaterally with 6-hydroxydopamine (6-OHDA), and the densities and levels of the mRNAs for D1 and D2 dopamine receptors were determined. The results showed that 6-OHDA caused significant reductions in D1 dopamine receptors and in D1 dopamine receptor mRNA in dorsolateral and dorsomedial regions of the lesioned striatum. By contrast, 6-OHDA lesions caused significant increases in D2 dopamine receptors and in D2 dopamine receptor mRNA in dorsolateral and ventrolateral regions of the lesioned striatum. To assess the effects of 6-OHDA lesions on the rate of synthesis of D1 and D2 dopamine receptors, the irreversibly acting dopamine receptor antagonist 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) was administered, and the rate of recovery of these receptors determined. The lesions decreased the rate of synthesis of D1 dopamine receptors in dorsolateral striatum but increased the rate of synthesis of D2 dopamine receptors in dorsolateral striatum. Correlation of these molecular events with dopaminergic behaviors showed that the rate of recovery from EEDQ-induced cataleptic activity and the recovery from inhibition of quinpirole-induced rotational behavior was more rapid than the recovery of either the D1 or D2 dopamine receptor. These results suggest that dopaminergic denervation differentially affects the rate of synthesis of D1 and D2 dopamine receptors in mouse striatum, and that these alterations in the rates of synthesis of the receptors may be explained by corresponding alterations in the levels of the respective transcripts for these receptors.
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  • 7
    ISSN: 0362-1642
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Chemistry and Pharmacology
    Notes: Adenosine and its receptors have been the topic of many recent reviews ( 1Đ??26 ). These reviews provide a good summary of much of the relevant literatureĐ??including the older literature. We have, therefore, chosen to focus the present review on the insights gained from recent studies on genetically modified mice, particularly with respect to the function of adenosine receptors and their potential as therapeutic targets. The information gained from studies of drug effects is discussed in this context, and discrepancies between genetic and pharmacological results are highlighted.
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