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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spiny neurons in the neostriatum are highly vulnerable to ischemia. Enhancement of excitatory synaptic transmissions has been implicated in ischemia-induced excitotoxic neuronal death. Here we report that evoked excitatory postsynaptic currents in spiny neurons were potentiated after transient forebrain ischemia. The ischemia-induced potentiation in synaptic efficacy was associated with an enhancement of presynaptic release as demonstrated by an increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) and a decrease in the paired-pulse ratio. The amplitude of inward currents evoked by exogenous application of glutamate did not show significant changes after ischemia, suggesting that postsynaptic mechanism is not involved. The ischemia-induced increase in mEPSCs frequency was not affected by blockade of voltage-gated calcium channels, but it was eliminated in the absence of extracellular calcium. Bath application of ATP P2X receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) significantly reduced mEPSC frequency in ischemic neurons but had no effects on the control ones. Furthermore, the inhibitory effect of PPADS on ischemic neurons was abolished in Ca2+-free external solution. These results indicate that excitatory synaptic transmissions in spiny neurons are potentiated after ischemia via presynaptic mechanisms. Activation of P2X receptors and the consequent Ca2+ influx might contribute to the ischemia-induced facilitation of glutamate release.
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PMID:Enhancement of excitatory synaptic transmission in spiny neurons after transient forebrain ischemia. 1635 27

AMP-activated protein kinase (AMPK) plays a key role in the regulation of energy homeostasis and is activated in response to cellular stress, including hypoxia/ischemia and hyperglycemia. The stress events are accompanied by rapid release of extracellular nucleotides from damaged tissues or activated endothelial cells (EC) and platelets. We demonstrate that extracellular nucleotides (ATP, ADP, and UTP, but not UDP) and adenosine independently induce phosphorylation and activation of AMPK in human umbilical vein EC (HUVEC) by the mechanism that is not linked to changes in AMP:ATP ratio. HUVEC express NTPDases, as well as 5'-nucleotidase; hence, nucleotides can be metabolized to adenosine. However, inhibition of 5'-nucleotidase had no effect on ATP/ADP/UTP-induced phospho- rylation of AMPK, indicating that AMPK activation occurred as a direct response to nucleotides. Nucleotide-evoked phosphorylation of AMPK in HUVEC was mediated by P2Y1, P2Y2, and/or P2Y4 receptors, whereas P2Y6, P2Y11, and P2X receptors were not involved. The nucleotide-induced phosphorylation of AMPK was affected by changes in the concentration of intracellular Ca2+ and by Ca2+/calmodulin-dependent kinase kinase (CaMKK), although most likely it was not dependent on LKB1 kinase. Adenosine-induced phosphorylation of AMPK was not mediated by P1 receptors but required adenosine uptake by equilibrative nucleoside transporters followed by its (intracellular) metabolism to AMP. Moreover, adenosine effect was Ca2+ and CaMKK independent, although probably associated with upstream LKB1. We hypothesize that P2 receptors and adenosine transporters could be novel targets for the pharmacological regulation of AMPK activity and its downstream effects on EC function.
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PMID:Extracellular nucleotides and adenosine independently activate AMP-activated protein kinase in endothelial cells: involvement of P2 receptors and adenosine transporters. 1649 86

Extracellular adenosine 5'-triphosphate (ATP) was proposed to be an activity-dependent signaling molecule that regulates glia-glia and glia-neuron communications. ATP is a neurotransmitter of its own right and, in addition, a cotransmitter of other classical transmitters such as glutamate or GABA. The effects of ATP are mediated by two receptor families belonging either to the P2X (ligand-gated cationic channels) or P2Y (G protein-coupled receptors) types. P2X receptors are responsible for rapid synaptic responses, whereas P2Y receptors mediate slow synaptic responses and other types of purinergic signaling involved in neuronal damage/regeneration. ATP may act at pre- and postsynaptic sites and therefore, it may participate in the phenomena of long-term potentiation and long-term depression of excitatory synaptic transmission. The release of ATP into the extracellular space, e.g., by exocytosis, membrane transporters, and connexin hemichannels, is a widespread physiological process. However, ATP may also leave cells through their plasma membrane damaged by inflammation, ischemia, and mechanical injury. Functional responses to the activation of multiple P2 receptors were found in neurons and glial cells under normal and pathophysiological conditions. P2 receptor-activation could either be a cause or a consequence of neuronal cell death/glial activation and may be related to detrimental and/or beneficial effects. The present review aims at demonstrating that purinergic mechanisms correlate with the etiopathology of brain insults, especially because of the massive extracellular release of ATP, adenosine, and other neurotransmitters after brain injury. We will focus in this review on the most important P2 receptor-mediated neurodegenerative and neuroprotective processes and their beneficial modulation by possible therapeutic manipulations.
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PMID:P2 receptors and neuronal injury. 1664 49

P2X(7) receptors are ligand-gated ion channels, expressed as homo-oligomeric assemblies of individual subunits. They are widely distributed at immunocompetent cells of the central and peripheral nervous system and are believed to be primarily involved in host-defense reaction. However, a growing amount of evidence indicates that their signaling role in the brain is more widespread than previously anticipated. In this paper, we review the present knowledge on the structural and pharmacological features of the P2X(7) receptor, as well as its cell-type specific localization in the nervous system. Subsequently, the participation of P2X(7) receptors in distinct neuronal, astroglial and microglial functions are described. Finally, since they may play a prominent role in certain neurologic disorders, such as ischemia-reperfusion injury, Alzheimer's disease, spinal cord injury and sensory neuropathies, the pathological role and potential therapeutic exploitation of P2X(7) receptors are also discussed.
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PMID:P2X7 receptors in the nervous system. 1669 2

During transient global ischemia, the excessive accumulation of intracellular Ca2+ induced by several episodes triggers delayed neuronal death within the vulnerable CA1 region of the hippocampus after ischemia-reperfusion insults. Although P2X receptors provide an additional source of Ca2+ entry, little data are available that these receptors could modulate the performance of the ischemic neuronal death. Therefore, we investigated the roles of the P2X receptor in the ischemic neuronal damage associated with various sequelae of transient ischemia, and the effects of their antagonist on the ischemic insults. As the results, ischemic insults increased P2X receptor expression in the gerbil hippocampus. Neither vigabatrin (VGB) nor P2X receptor antagonists (suramin, pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid) protected against the delayed neuronal death in the CA1 region of the hippocampus after ischemia. However, the co-treatments of VGB and P2X receptor antagonists effectively prevent ischemia-induced neurodegeneration. Therefore, these findings suggest that blockade of the P2X receptor accompanied by activation of GABAergic inhibition may play an important role in the neuroprotection against ischemic insults.
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PMID:The co-treatments of vigabatrin and P2X receptor antagonists protect ischemic neuronal cell death in the gerbil hippocampus. 1697 98

The function of oligodendrocytes is to myelinate CNS axons. Oligodendrocytes and the axons they myelinate are functional units, and neurotransmitters released by axons can influence all stages of oligodendrocyte development via calcium dependent mechanisms. Some of the clearest functional evidence is for adenosine, ATP, and glutamate, which are released by electrically active axons and regulate the migration and proliferation of oligodendrocyte progenitor cells and their differentiation into myelinating oligodendrocytes. Glutamate and ATP, released by both axons and astrocytes, continue to mediate Ca(2+) signaling in mature oligodendrocytes, acting via AMPA and NMDA glutamate receptors, and heterogeneous P2X and P2Y purinoceptors. Physiological signalling between axons, astrocytes, and oligodendrocytes is likely to play an important role in myelin maintenance throughout life. Significantly, ATP- and glutamate-mediated Ca(2+) signaling are also major components of oligodendrocyte and myelin damage in numerous pathologies, most notably ischemia, injury, periventricular leukomalacia, and multiple sclerosis. In addition, NG2-expressing glia (synantocytes) in the adult CNS are highly reactive cells that respond rapidly to any CNS insult by a characteristic gliosis, and are able to regenerate oligodendrocytes and possibly neurons. Glutamate and ATP released by neurons and astrocytes evoke Ca(2+) signaling in NG2-glia (synantocytes), and it is proposed these regulate their differentiation capacity and response to injury. In summary, clear roles have been demonstrated for neurotransmitter-mediated Ca(2+) signaling in oligodendrocyte development and pathology. A key issue for future studies is to determine the physiological roles of neurotransmitters in mature oligodendrocytes and NG2-glia (synantocytes).
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PMID:Neurotransmitter-mediated calcium signalling in oligodendrocyte physiology and pathology. 1700 95

Recombinant human P2X(7) receptors, C-terminally labelled with enhanced green fluorescent protein (P2X(7)-EGFP), were transiently expressed in HEK293 cells. Activation of these receptors by their preferential agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP) induced inward currents and propidium ion uptake indicating the opening of cationic channels and of large pores permeable for dye molecules, respectively. Two mutants of P2X(7) receptors (P2X(7)-EGFP-I568N, -E496A) representing polymorphisms in the P2X(7) gene known to interfere with normal receptor-trafficking and with optimal assembly of its subunits, responded with much lower current amplitudes to BzATP than their wild-type counterpart. Similarly, the normal propidium ion uptake induced by BzATP at the wild-type P2X(7) receptor was abolished by the two mutants. Confocal laser scanning microscopy indicated that in vitro ischemia of 12h duration increased the integration of P2X(7)-EGFP, but not of its two mutants, into the plasma membrane of HEK293 cells. Further, this ischemic stimulus facilitated the current response to BzATP in HEK293 cells permanently transfected with P2X(7) receptors. Finally, the fluorescence intensity per cell measured by flow cytometry and P2X(7) antibodies directed against an extracellular, but not an intracellular epitope of the receptor, were also increased. In conclusion, P2X(7) receptors may alter their trafficking properties during ischemia and thereby contribute to the ATP-induced damage of various cell-types including neurons.
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PMID:Oxygen/glucose deprivation increases the integration of recombinant P2X7 receptors into the plasma membrane of HEK293 cells. 1761 31

In this work, we mainly used the organotypic model of rat hippocampus to demonstrate the protective role of the P2 receptor antagonist trinitrophenyl-adenosine-triphosphate (TNP-ATP) during oxygen/glucose deprivation. Among the P2X receptors that TNP-ATP specifically blocks, mainly P2X1 seems to be involved in the processes of cell damage after oxygen/glucose deprivation. P2X1 receptor is strongly and transiently up-regulated in 24 h after an ischemic insult on structures likely corresponding to mossy fibers and Schaffer collaterals of CA1-3 and dentate gyrus. Furthermore, P2X1 receptor is down-regulated by pharmacological treatment with TNP-ATP, which is also found neuroprotective against ischemic cell death. Morphological studies conducted through immunofluorescence and confocal analysis in primary organotypic, in dissociated cultures, and in adult rat in vivo demonstrated the neuronal colocalization of P2X1 protein with neurofilament light chain and neuronal nuclei immunoreactivity in myelinated and unmyelinated fibers of both granular and pyramidal neurons. In conclusion, with this work, we proved the neuronal distribution of P2X1 receptor in hippocampus, and we presented evidence for a potential disadvantageous role of its expression during the path of in vitro ischemia.
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PMID:P2 receptor antagonist trinitrophenyl-adenosine-triphosphate protects hippocampus from oxygen and glucose deprivation cell death. 1762 Apr 57

The aim of the present study was to explore whether endogenous activation of different purine receptors by ATP and adenosine contributes to or inhibits excess glutamate release evoked by ischemic-like conditions in rat hippocampal slices. Combined oxygen-glucose deprivation (OGD) elicited a substantial, [Ca(2+)](o)-independent release of [(3)H]glutamate, which was tetrodotoxin (1 microM)-sensitive and temperature-dependent. The P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 0.1-10 microM), and the selective P2X(7) receptor antagonist Brilliant Blue G (1-100 nM), decreased OGD-evoked [(3)H]glutamate efflux indicating that endogenous ATP facilitates ischemia-evoked glutamate release. The selective A(1)-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.1-250 nM) and the selective A(2A) receptor antagonists 4-(2-[7-amino-2-)2-furyl(triazolo-[1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385, 0.1-20 nM) and 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261, 2-100 nM) decreased OGD-evoked [(3)H]glutamate efflux, indicating that endogenous adenosine also facilitates glutamate release under these conditions. The effect of DPCPX and ZM241385 was reversed, whereas the action of P2 receptor antagonists was potentiated by the selective ecto-ATPase inhibitor 6-N,N-diethyl-D-beta,gamma-dibromomethyleneATP (ARL67156, 50 microM). The binding characteristic of the A(2A) ligand [(3)H]CGS21680 to hippocampal membranes did not change significantly in response to OGD. Taken together these data suggest that while A(1) receptors might became desensitized, A(2A) and P2X receptor-mediated facilitation of glutamate release by endogenous ATP and its breakdown product adenosine remains operational under long-term OGD. Therefore the inhibition of P2X/A(2A) receptors rather than the stimulation of A(1) adenosine receptors could be an effective approach to attenuate glutamatergic excitotoxicity and thereby counteract ischemia-induced neurodegeneration.
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PMID:Purinergic modulation of glutamate release under ischemic-like conditions in the hippocampus. 1785 Sep 81

P2 purinoceptor modulation of injury during ischemia-reperfusion was studied in murine hearts. Effects of P2 agonism or antagonism, and interstitial accumulation of P2 agonists (UTP, ATP, and ADP), were assessed in Langendorff perfused hearts during 20 min of ischemia and 45 min of reperfusion. In control hearts, ventricular pressure development recovered to 68 +/- 4 mm Hg (63 +/- 3% baseline), diastolic pressure remained elevated (23 +/- 2 mm Hg), and 26 +/- 4 U/g lactate dehydrogenase (LDH) was released during reperfusion, evidencing necrosis. Treatment with 250 nM UTP improved pressure development (85 +/- 5 mm Hg, or 77 +/- 2%) and reduced diastolic contracture (by approximately 70%, to 7 +/- 1 mm Hg) and LDH loss (by approximately 60%, to 11 +/- 2 U/g). In contrast, P2Y1 agonism with 50 nM 2-methyl-thio-ATP (2-MeSATP) was ineffective. In the presence of the P2Y antagonist suramin (10 or 200 microM), UTP no longer improved postischemic outcomes. Ischemia also substantially elevated interstitial [UTP], [ATP], and [ADP], potentially activating P2 receptors. This was supported in part by effects of antagonists: 200 microM suramin worsened LDH efflux (53 +/- 9 IU/g) and contractile dysfunction (41 +/- 2 mm Hg diastolic pressure; 28 +/- 3 mm Hg developed pressure), as did P2Y antagonism with either 10 or 100 microM reactive blue 2. However, a 10 microM concentration of suramin failed to alter outcome. P2X antagonism with 10 microM pyridoxal phosphate-6-azo-(benzene-2,4-disulfonic acid and P2X1-selective pyridoxal-alpha5-phosphate-6-phenylazo-4'-carboxylic acid (MRS2159) (30 microM) was ineffective. Data collectively support cardioprotection with low concentrations of UTP, and they are consistent with P2Y2 involvement. Endogenous nucleotides may also play a protective role, as evidenced by effects of P2 antagonists, although this warrants further investigation.
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PMID:P2 purinoceptor-mediated cardioprotection in ischemic-reperfused mouse heart. 1785 79


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