Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kanebo is investigating KB-R7943, a Na+/Ca2+ ion exchange inhibitor, for the potential treatment of ischemia and reperfusion injury. It inhibited the outward Na+/Ca2+ exchange current (iNCX) more potently than the inward current under unidirectional flow conditions; however, inward and outward current were inhibited equally under bidirectional conditions. The drug was a competitive inhibitor to external calcium, and the inhibition was reversible with a recovery t1/2 of about 30 s. The mammalian Na+/Ca2+ exchanger forms a multigene family of homologous proteins comprising three isoforms, NCX1, NCX2 and NCX3. By examining chimeric constructs between NCX1 and NCX3 expressed in CCL39 cells, it has been demonstrated that it is the conserved internal repeat regions (alpha-1 and alpha-2) of the exchanger that are critical for the drug's action.
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PMID:KB-R7943. Kanebo. 1189 38

To investigate the effect of chronic global cerebral ischemia on gene expression of Na(+)/Ca(2+) exchanger isoforms NCX1, NCX2 and NCX3 in rat brain. Chronic global cerebral ischemia was induced by bilateral common carotid artery ligation (BCAL) in rats for 1 week, 2 weeks and 4 weeks, respectively. Morris water maze was applied to demonstrate the credibility of BCAL models. After BCAL for 4 weeks, there was learning and memory deficiency that the latency and distance of BCAL group were longer than those of sham group from the second trial to tenth trial in hidden platform trials. Reverse transcription-polymerase chain reaction was used to assess the gene expression of Na(+)/Ca(2+) exchanger isoforms at mRNA level in cerebral cortex and hippocampus. For NCX1, its expression was decreased by 35%, 54% and 27% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively; For NCX2, its expression was decreased by 41%, 29% and 12% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively; For NCX3, its expression was decreased by 29%, 27% and 12% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively. However, in hippocampus, the expressions of NCX1 and NCX3 did not change significantly in different BCAL groups. NCX2 was increased by 60% in BCAL for 1 week only, but did not change significantly in BCAL for 2 weeks or 4 weeks. The study indicated that brain ischemia regulated gene expression levels of Na(+)/Ca(2+) exchanger isoforms especially in cerebral cortex.
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PMID:Altered gene expression of Na+/Ca2+ exchanger isoforms NCX1, NCX2 and NCX3 in chronic ischemic rat brain. 1237 75

Dysregulation of sodium [Na+]i and calcium [Ca2+]i homeostasis plays a pivotal role in the pathophysiology of cerebral ischemia. Three gene products of the sodium-calcium exchanger family NCX1, NCX2, and NCX3 couple, in a bidirectional way, the movement of these ions across the cell membrane during cerebral ischemia. Each isoform displays a selective distribution in the rat brain. To determine whether NCX gene expression can be regulated after cerebral ischemia, we used NCX isoform-specific antisense radiolabeled probes to analyze, by radioactive in situ hybridization histochemistry, the pattern of NCX1, NCX2, and NCX3 transcripts in the ischemic core, periinfarct area, as well as in nonischemic brain regions, after 6 and 24 h of permanent middle cerebral artery occlusion (pMCAO) in rats. We found that in the focal region, comprising divisions of the prefrontal, somatosensory, and insular cortices, all three NCX transcripts were downregulated. In the periinfarct area, comprising part of the motor cortex and the lateral compartments of the caudate-putamen, NCX2 messenger ribonucleic acid (mRNA) was downregulated, whereas NCX3 mRNA was significantly upregulated. In remote nonischemic brain regions such as the prelimbic and infralimbic cortices, and tenia tecta, both NCX1 and NCX3 transcripts were upregulated, whereas in the medial caudate-putamen only NCX3 transcripts increased. In all these intact regions, NCX2 signal strongly decreased. These results indicate that NCX gene expression is regulated after pMCAO in a differential manner, depending on the exchanger isoform and region involved in the insult. These data may provide a better understanding of each NCX subtype's pathophysiologic role and may allow researchers to design appropriate pharmacological strategies to treat brain ischemia.
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PMID:Permanent focal brain ischemia induces isoform-dependent changes in the pattern of Na+/Ca2+ exchanger gene expression in the ischemic core, periinfarct area, and intact brain regions. 1610 87

The specific role played by NCX1, NCX2, and NCX3, the three isoforms of the Na+/Ca2+ exchanger (NCX), has been explored during hypoxic conditions in BHK cells stably transfected with each of these isoforms. Six major findings emerged from the present study: (1) all the three isoforms were highly expressed on the plasma membranes of BHK cells; (2) under physiological conditions, the three NCX isoforms showed similar functional activity; (3) hypoxia plus reoxygenation induced a lower increase of [Ca2+]i in BHK-NCX3-transfected cells than in BHK-NCX1- and BHK-NCX2-transfected cells; (4) NCX3-transfected cells were more resistant to chemical hypoxia plus reoxygenation than NCX1- and NCX2-transfected cells. Interestingly, such augmented resistance was eliminated by CBDMD (10 microM), an inhibitor of NCX and by the specific silencing of the NCX3 isoform; (5) chemical hypoxia plus reoxygenation produced a loss of mitochondrial membrane potential in NCX1- and NCX2-transfected cells, but not in NCX3-transfected cells; (6) the forward mode of operation in NCX3-transfected cells was not affected by ATP depletion, as it occurred in NCX1- and NCX2-transfected cells. Altogether, these results indicate that the brain specifically expressed NCX3 isoform more significantly contributes to the maintenance of [Ca2+]i homeostasis during experimental conditions mimicking ischemia, thereby preventing mitochondrial delta psi collapses and cell death.
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PMID:BHK cells transfected with NCX3 are more resistant to hypoxia followed by reoxygenation than those transfected with NCX1 and NCX2: Possible relationship with mitochondrial membrane potential. 1734 9

Over the last few years, although extensive studies have focused on the relevant function played by the sodium-calcium exchanger (NCX) during focal ischemia, a thorough understanding of its role still remains a controversial issue. We explored the consequences of the pharmacological inhibition of this antiporter with conventional pharmacological approach, with the synthetic inhibitory peptide, XIP, or with an antisense strategy on the extent of brain damage induced by the permanent occlusion of middle cerebral artery (pMCAO) in rats. Collectively, the results of these studies suggest that ncx1 and ncx3 genes could be play a major role to limit the severity of ischemic damage probably as they act to dampen [Na+]i and [Ca2+]i overload. This mechanism seems to be normally activated in the ischemic brain as we found a selective upregulation of NCX1 and NCX3 mRNA levels in regions of the brain surviving to an ischemic insult. Despite this transcript increase, NCX1, NCX2, and NCX3 proteins undergo an extensive proteolytic degradation in the ipsilateral cerebral hemisphere. All together these results suggest that a rescue program centered on an increase NCX function and expression could halt the progression of the ischemic damage. On the basis of this evidence we directed our attention to the understanding of the transductional and transcriptional pathways responsible for NCX upregulation. To this aim, we are studying whether the brain isoform of Akt, Akt1, which is a downstream effector of neurotrophic factors, such as NGF can, in addition to affecting the other prosurvival cascades, also exert its neuroprotective effect by modulating the expression and activity of ncx1, ncx2, and ncx3 gene products.
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PMID:ncx1, ncx2, and ncx3 gene product expression and function in neuronal anoxia and brain ischemia. 1744 81

Sodium/calcium exchangers are neuronal plasma membrane transporters, which by coupling Ca2+ and Na+ fluxes, may play a relevant role in brain ischemia. The exchanger gene superfamily comprises two arms: the K+-independent (NCX) and K+-dependent (NCKX) exchangers. In the brain, three different NCX (NCX1, NCX2, NCX3) and three NCKX (NCKX2, NCKX3, NCKX4) family members have been described. Up to now, no sutides about the role played by NCKX proteins in cerebral ischemia have been published. The aim of the present study was to investigate the role of NCKX2 in an in vivo model of permanent middle cerebral artery occlusion (pMCAO). The role of this protein in the development of ischemic damage was assessed by knocking-down its expression with an antisense oligodeoxynucleotide (AS-ODN), intracerebroventricularly infused by an osmotic minipump for 48 h, starting from 24 h before pMCAO. The results showed that NCKX2 knocking-down by using antisense strategy increased the extent of the ischemic lesion. The results of this study suggest that NCKX2 could exert a neuroprotective effect during ischemic injury.
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PMID:Involvement of the potassium-dependent sodium/calcium exchanger gene product NCKX2 in the brain insult induced by permanent focal cerebral ischemia. 1744 91

Na(+)/Ca(2+) exchanger (NCX), by mediating Na(+) and Ca(2+) fluxes bi-directionally, assumes a role in controlling the Ca(2+) homeostasis in the ischemic brain. It has been suggested that the three isoforms of NCX (NCX1, 2 and 3) may be differentially involved in permanent cerebral ischemia. However, the role of NCX2 has not been defined in ischemic reperfusion injury after a transient focal cerebral ischemia. Furthermore, it is not known whether NCX2 imports or exports intracellular Ca(2+) ([Ca(2+)](i)) following ischemia and reperfusion. To define the role of NCX2 in ischemia and reperfusion, we examined mice lacking NCX2, in vivo and in vitro. After an in vitro ischemia, a significantly slower recovery in population spike amplitudes, a sustained elevation of [Ca(2+)](i) and an increased membrane depolarization were developed in the NCX2-deficient hippocampus. Moreover, a transient focal cerebral ischemia in vivo produced a larger infarction and more cell death in the NCX2-deficient mouse brain. In particular, in the wild type brain, NCX2-expressing neurons were largely spared from cell death after ischemia. Our results suggest that NCX2 exports Ca(2+) in ischemia and thus protects neuronal cells from death by reducing [Ca(2+)](i) in the adult mouse brain.
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PMID:Na(+)/Ca(2+) exchanger 2 is neuroprotective by exporting Ca(2+) during a transient focal cerebral ischemia in the mouse. 1788 63

The Na(+)/Ca(2+) exchanger (NCX) is a bidirectional transporter that normally extrudes Ca(2+) from the cell (forward mode), but also brings Ca(2+) into the cell (reverse mode) under special conditions such as intracellular Na(+) (Na(+)(i)) accumulation or membrane depolarization. There are three mammalian NCX isoforms: NCX1 is widely expressed in the heart, kidney, brain, blood vessels, and so on; whereas the expression of NCX2 and NCX3 is limited mainly to the brain and skeletal muscle. The pharmacology of NCX inhibitors has been studied extensively since the development of KB-R7943, a prototype benzyloxyphenyl NCX inhibitor, in 1996. Currently, experiments are actively progressing with more selective inhibitors: SEA0400, SN-6, and YM-244769. Intriguingly, the inhibitory potency of benzyloxyphenyl NCX inhibitors is directly coupled to the rate of Na(+)(i)-dependent inactivation. Therefore, the benzyloxyphenyl inhibitors are apparently dormant during the forward mode under normal conditions (low Na(+)(i)), but become effective during the reverse mode under pathological conditions (high Na(+)(i)). This should be an ideal profile for calcium regulators against Na(+)(i)-related diseases, such as ischemia/reperfusion injuries, salt-dependent hypertension, and digitalis arrhythmia. Existing ion channel blockers, such as amiodarone, dronedarone, bepridil, aprindine, and cibenzoline, have been found to have an NCX inhibitory action. It is possible that this property is partly responsible for their antiarrhythmic and cardioprotective effects. This article presents the characteristics of selective and non-selective NCX inhibitors and their therapeutic potential as a new calcium regulator.
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PMID:Na+/Ca2+ exchange inhibitors: a new class of calcium regulators. 1789 59

There is increasing evidence that the sodium-calcium exchanger (NCX) subtypes, NCX1, NCX2 and NCX3 play an important role in intracellular calcium homeostasis/dysregulation following cerebral ischemia. In the present study we examined NCX1, NCX2 and NCX3 protein levels in the rat hippocampus at 3, 6, 12, 18, 24 and 48 h following a 3 min and 8 min duration of global cerebral ischemia. We observed that NCX1 protein levels were significantly increased by 22.3% and 20.6% at the 6 and 12 h respective time points following a 3 min duration of global ischemia, while NCX2 and NCX3 protein levels remained relatively constant. Following a 8 min duration of global ischemia, NCX1 protein levels remained relatively constant, while NCX2 protein levels were down-regulated by 6.9%, 10.8%, 14.4% and 10.3% at the 6, 18, 24 and 48 h respective time points, and NCX3 protein levels were up-regulated by 22.1% at the 18 h time point. Taken together, our results show that NCX subtype protein expression is sensitive to cerebral ischemia, and indicates that changes in NCX activity may be playing an important role in calcium maintenance and neuronal outcome following ischemia.
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PMID:Na+/Ca2+ exchanger subtype (NCX1, NCX2, NCX3) protein expression in the rat hippocampus following 3 min and 8 min durations of global cerebral ischemia. 1803 93

It has been recently shown that a short sublethal brain ischemia subsequent to a prolonged harmful ischemic episode may confer ischemic neuroprotection, a phenomenon termed ischemic postconditioning. Na(+)/Ca(2+) exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are plasma membrane ionic transporters widely distributed in the brain and involved in the control of Na(+) and Ca(2+) homeostasis and in the progression of stroke damage. The objective of this study was to evaluate the role of these three proteins in the postconditioning-induced neuroprotection. The NCX protein and mRNA expression was evaluated at different time points in the ischemic temporoparietal cortex of rats subjected to tMCAO alone or to tMCAO plus ischemic postconditioning. The results of this study showed that NCX3 protein and ncx3 mRNA were upregulated in those brain regions protected by postconditioning treatment. These changes in NCX3 expression were mediated by the phosphorylated form of the ubiquitously expressed serine/threonine protein kinase p-AKT, as the p-AKT inhibition prevented NCX3 upregulation. The relevant role of NCX3 during postconditioning was further confirmed by results showing that NCX3 silencing, induced by intracerebroventricular infusion of small interfering RNA (siRNA), partially reverted the postconditioning-induced neuroprotection. The results of this study support the idea that the enhancement of NCX3 expression and activity might represent a reasonable strategy to reduce the infarct extension after stroke.
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PMID:The NCX3 isoform of the Na+/Ca2+ exchanger contributes to neuroprotection elicited by ischemic postconditioning. 2062 98


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