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

Leukocytes play an important role in the development of ischemia/reperfusion injury. Recent work in our laboratory has demonstrated that a mixture of synthetic fibronectin peptides to leukocyte adhesion molecules reduces ischemic brain damage after transient focal cerebral ischemia. The purpose of this study was to evaluate the efficacy of the individual peptides on leukocyte accumulation, infarct size, and neurological outcome in rats subjected to 1 h of cerebral ischemia and 48 h of reperfusion. Thirty-five animals were divided into five groups: transient ischemia without treatment (Group I), treatment with arginyl-glycyl-aspartic acid (RGD) peptide (Group II), connecting segment (CS)-1 peptide (Group III), fibronectin (FN)-C/H-V peptide (Group IV), and scrambled FN-C/H-V peptide (Group V). Groups III and IV showed a significant decrease in the degree of leukocyte infiltration in the lesion and in the infarct size (p < 0.05) when compared to Groups I, II, and V. The neurological grade of Groups III and IV was significantly better than in Groups I, II, and V at 48 h after reperfusion (p < 0.01). Thus, in addition to demonstrating the potential efficacy of synthetic peptides as therapeutic agents for ischemia-reperfusion, these results also offer new insights into the mechanisms of leukocyte arrest and recruitment in ischemia/reperfusion injury.
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PMID:Neuronal protection from cerebral ischemia by synthetic fibronectin peptides to leukocyte adhesion molecules. 889 83

There are significant Ca2+-independent increases in extracellular glutamate and aspartate during various CNS insults such as ischemia and anoxia. However, the cellular sources of such presumed nonvesicular excitatory amino acid (EAA) release have not been established. To further explore potential mechanisms and sites for EAA release, we studied the release of preloaded [3H]-D-aspartate from primary cultured astrocytes prepared from the cerebral cortices of rat pups. Two phases of release were seen in response to raised KCl. The first phase was small and transient, and the second phase was slower and increased progressively. The initial phase of [3H]-D-aspartate release was greatly enhanced by ouabain pretreatment and was inhibited when astrocytes were preexposed to the EAA transport inhibitor threo-hydroxy beta-aspartic acid (THBA). Neither of these manipulations affected the second release component. The second phase of release was inhibited by an anion channel blocker, L-644,711, which is known to inhibit hypotonic swelling-induced release of EAA. Ouabain also resulted in the first phase of release occurring at lower [K+]o. Omission of Ca2+ had no effect on either phase of [3H]-D-aspartate release. These results support the hypothesis that the first component of release in cultured astrocytes is a reversal of the glutamate transporter, and the second component is a result of high KCl-induced swelling. Because marked increases in [K+]o are well established in CNS pathologies such as ischemia, such release may represent a significant source for the increased extracellular EAAs seen in such conditions.
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PMID:Release of [3H]-D-aspartate from primary astrocyte cultures in response to raised external potassium. 898 8

Glutamate receptor antagonists are protective in animal models of focal cerebral ischemia. Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2, 4-triazine) is an anticonvulsant drug that blocks voltage-gated sodium channels and inhibits the ischemia-induced release of glutamate. Experiments in primary neuronal cultures implicate nitric oxide (NO) as a mediator of glutamatergic neurotoxicity acting via N-Methyl-D-Aspartate (NMDA) receptors. The effect of glutamate release inhibitor, Lamotrigine upon NO and cGMP production has been examined in focal cerebral ischemia in rats. Focal cerebral ischemia was produced by the permanent occlusion of right middle cerebral artery (MCA) in urethane anesthetized rats. A number of indicators of brain NO production (nitrite, cGMP) were determined in ipsilateral and contralateral cerebral cortex and cerebellum after 0, 10, 60 min of focal cerebral ischemia. The same parameters were measured in rats treated with Lamotrigine (20 mg/kg, i.p.) 30 min before or just after the occlusion of the right MCA.
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PMID:Effects of Lamotrigine on brain nitrite and cGMP levels during focal cerebral ischemia in rats. 908 81

Repetitive spreading depression (SD) waves, involving depolarization of neurons and astrocytes and up-regulation of glucose consumption, is thought to lower the threshold of neuronal death during and immediately after ischemia. Using rat models for SD and focal ischemia we investigated the expression of cyclooxygenase-1 (COX-1), the constitutive form, and cyclooxygenase-2 (COX-2), the inducible form of a key enzyme in prostaglandin biosynthesis and the target enzymes for nonsteroidal anti-inflammatory drugs. Whereas COX-1 mRNA levels were undetectable and uninducible, COX-2 mRNA and protein levels were rapidly increased in the cortex, especially in layers 2 and 3 after SD and transient focal ischemia. The cortical induction was reduced by MK-801, an N-methyl-D-aspartic acid-receptor antagonist, and by dexamethasone and quinacrine, phospholipase A2 (PLA2) inhibiting compounds. MK-801 acted by blocking SD whereas treatment with PLA2 inhibitors preserved the wave propagation. NBQX, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-receptor antagonist, did not affect the SD-induced COX-2 expression, whereas COX-inhibitors indomethacin and diclofenac, as well as a NO synthase-inhibitor, NG-nitro-L-arginine methyl ester, tended to enhance the COX-2 mRNA expression. In addition, ischemia induced COX-2 expression in the hippocampal and perifocal striatal neurons and in endothelial cells. Thus, COX-2 is transiently induced after SD and focal ischemia by activation of N-methyl-D-aspartic acid-receptors and PLA2, most prominently in cortical neurons that are at a high risk to die after focal brain ischemia.
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PMID:Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. 917 47

Ca2+-activated K+ currents in rat locus coeruleus neurons induced by experimental ischemia, anoxia, and hypoglycemia. J. Neurophysiol. 78: 2674-2681, 1997. The effects of metabolic inhibition on membrane currents and N-methyl--aspartic acid (NMDA)-induced currents were investigated in dissociated rat locus coeruleus (LC) neurons by using the nystatin perforated patch recording mode under voltage-clamp conditions. Changes in the intracellular Ca2+ concentration ([Ca2+]i) during the metabolic inhibition were also investigated by using the microfluometry with a fluorescent probe, Indo-1. Removal of both the oxygen and glucose (experimental ischemia), deprivation of glucose (hypoglycemia), and a blockade of electron transport by sodium cyanide (NaCN) or a reduction of the mitochondrial membrane potential with carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazone(FCCP) as experimental anoxia all induced a slowly developing outward current (IOUT) at a holding potential of -40 mV. The application of 10(-4) M NMDA induced a rapid transient peak and a successive steady state inward current and a transient outward current immediately after washout. All treatments related to metabolic inhibition increased the NMDA-induced outward current(INMDA-OUT) and prolonged the one-half recovery time of INMDA-OUT. The reversal potentials of both IOUT and INMDA-OUT were close to the K+ equilibrium potential (EK) of -82 mV. Either charybdotoxin or tolbutamide inhibited the IOUT and INMDA-OUT, suggesting the contribution of Ca2+-activated and ATP-sensitive K+ channels, even though the inhibitory effect of tolbutamide gradually diminished with time. Under the metabolic inhibition, the basal level of [Ca2+]i was increased and the one-half recovery time of the NMDA-induced increase in [Ca2+]i was prolonged. The IOUT induced by NaCN was inhibited by a continuous treatment of thapsigargin but not by ryanodine, indicating the involvement of inositol 1,4, 5-trisphosphate (IP3)-induced Ca2+ release (IICR) store. These findings suggest that energy deficiency causes Ca2+ release from the IICR store and activates continuous Ca2+-activated K+ channels and transient ATP-sensitive K+ channels in acutely dissociated rat LC neurons.
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PMID:Ca2+-activated K+ currents in rat locus coeruleus neurons induced by experimental ischemia, anoxia, and hypoglycemia. 935 17

Ischemia is the most common cause of acute renal failure (ARF). In the last decade, several new and important pathophysiological mechanisms that underlie the renal dysfunction have been discovered. These pathophysiological mechanisms include the role of both calcium and calcium-dependent enzymes, oxidant stress, loss of polarity of the tubular cell, tubular obstruction and arginine-glycine-aspartic acid (RGD) peptides, neutrophils, intracellular adhesion molecules (ICAM), and growth factors. A better understanding of tubular and vascular mechanisms has led to therapeutic studies in animals and clinical trials in humans. In this review, the pathophysiology of ischemic ARF will be correlated with the rationale for both current and future therapies.
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PMID:Emerging therapies for acute renal failure. 937 85

[(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low affinity uncompetitive N-methyl-D-aspartic acid receptor antagonist that was tested in animal models of anoxia and ischemia. Pretreatment of rodents with ARL 15896AR extended survival time during exposure to hypoxia. With the rat four-vessel occlusion model of global ischemia (20 min), oral dosing commencing at reflow, resulted in significant protection of the CA1 hippocampal neurons. ARL 15896AR was, however, ineffective in the rat two-vessel occlusion model and in the gerbil models of forebrain ischemia, the latter due to an inability to attain suitable plasma levels. In the spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) (2 hr plus 22 hr reflow), acute dosing with ARL 15896AR (i.p.) beginning from 30 min before or up to 1 hr post-MCAO significantly reduced cortical infarct volume. The ability of ARL 15896AR to influence infarct size, as well as functional correlates was examined in SHR after 90 min of MCAO. T2 weighted magnetic resonance images taken at 2 and 6 days post-MCAO revealed significantly smaller lesion sizes in the group receiving injections with ARL 15896AR beginning 30 min after occlusion. Spontaneously hypertensive rats were subsequently tested (30-42 days post-MCAO) and found to be deficient in skilled use of the forepaws (staircase test). The contralateral forepaw was most severely impaired, however, ARL 15896AR treatment prevented motor impairment in only the ipsilateral forepaw. Histopathological examination of cortical infarct size was unremarkable between treated and control rats. The findings indicate that ARL 15896AR exhibits neuroprotection in global and focal models of ischemia
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PMID:-(S)-Alpha-phenyl-2-pyridine-ethanamine Dihydrochloride-, a low affinity uncompetitive N-methyl-D-aspartic acid antagonist, is effective in rodent models of global and focal ischemia. 940 17

To elucidate the role of astrocytes in the stress response of the central nervous system to ischemia, early gene expression was examined in rat cultured astrocytes after the exposure to hypoxia/reoxygenation, and we have previously cloned a novel RNA binding protein, RA301, from the reoxygenated astrocytes. Furthermore, we have now cloned a new gene for RA301 binding protein, termed YT521, by a yeast two-hybrid screening technique to explore RA301 functions. The YT521 cDNA is about 3200 bp long with an open reading frame encoding 712 amino acids. This amino acid sequence contains arginine-aspartic acid-glutamic acid rich region and glutamic acid rich one, and has a low degree of homology with RNA binding proteins such as U1-70k. Northern blot analysis revealed that YT521 mRNA expression was up-regulated in reoxygenated astrocytes. Induction of YT521 mRNA was mediated by endogenously generated reactive oxygen species, as it was suppressed by treatment of the cells with diphenyl iodonium which blocks oxygen-free radical formation by astrocytes. These expression patterns resembled those of RA301 mRNA. Far Western blot analysis showed that YT521 protein was not only interacting with RA301 protein, but also with SC35 and SF2, both of which are splicing factors. These results suggest that YT521 is a novel candidate for RNA splicing-related protein.
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PMID:Cloning of a gene, YT521, for a novel RNA splicing-related protein induced by hypoxia/reoxygenation. 947 74

Previous study demonstrated that, in hippocampal neuron/glia mixed cultures, glucocorticoids (GCs) enhanced extracellular overflow of [3H]D-aspartate [3H]D-Asp) by decreasing its uptake, thereby aggravating cell death during cyanide-induced ischemia. Since neuronal and glial cells respond to ischemic insult and GC differently, this study further evaluated the relative significance of these cells in GC endangering ischemic cell death. Using D-[2,3-3H]aspartic acid ([3H]D-Asp) as a tracer, it was found that corticosterone (CORT, the physiological GC in rat) enhanced the overflow of extracellular [3H]D-Asp in astrocyte cultures and, to a lesser extent, in neuron-enriched cultures during cyanide-induced ischemia. Analysis of [3H]D-Asp uptake kinetics indicates that CORT reduced the maximum uptake rate in cultured astrocyte, but not in neurons, after cyanide exposure. It is concluded that, during cyanide-induced ischemia, CORT might mainly the ability of astrocytes to clear excitatory amino acids from the synapse, thus exacerbating the damaging cascade of these amino acids.
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PMID:Corticosterone exacerbates cyanide-induced cell death in hippocampal cultures: role of astrocytes. 958 16

Glutamate receptor-mediated responses were investigated by using a whole-cell recording and an intracellular calcium ion ([Ca2+]i) imaging in gerbil postischemic hippocampal slices prepared at 1, 3, 6, 9, 12, and 24 hours after 5-minute ischemia. Bath application of N-methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate showed that NMDA-, AMPA- and kainate-induced currents were enhanced in postischemic CA1 pyramidal neurons at 1 to 12 hours after 5-minute ischemia. NMDA and non-NMDA receptor-mediated excitatory postsynaptic currents (EPSC) were examined in postischemic CA1 pyramidal neurons at 3 hours after 5-minute ischemia to confirm whether synaptic responses are enhanced in the postischemic CA1 pyramidal neurons. The amplitudes of NMDA- and non-NMDA-receptor-mediated EPSC were enhanced in the postischemic CA1 pyramidal neurons. NMDA-, AMPA-, and kainate-induced [Ca2+]i elevations were also examined to determine whether the enhancement of currents is accompanied by the enhancement of [Ca2+]i elevation. The enhancements of NMDA-, AMPA-, and kainate-induced [Ca2+]i elevations were shown in the postischemic CA1. These results indicate that NMDA and non-NMDA receptor-mediated responses are persistently enhanced in the CA1 pyramidal neurons 1 to 12 hours after transient ischemia, and suggest that the enhancement of glutamate receptor-mediated responses may act as one of crucial factors in the pathologic mechanism responsible for leading postischemic CA1 pyramidal neurons to irreversible neuronal injury.
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PMID:Postischemic enhancements of N-methyl-D-aspartic acid (NMDA) and non-NMDA receptor-mediated responses in hippocampal CA1 pyramidal neurons. 977 85


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