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

In this study, we determined whether the retina cell death observed in response to an ischemic-like insult is related to an overactivation of the ionotropic glutamate receptors and/or to a collapse of the energy levels. Cultured chick retina cells were submitted to 'chemical ischemia' by metabolic inhibition with sodium cyanide and iodoacetic acid, which block oxidative phosphorylation and glycolysis, respectively. The assessment of neuronal injury was made spectrophotometrically by quantification of cellularly reduced MTT, which gives information about mitochondrial function, or by staining with fluorescein diacetate (FDA), which correlates with changes in the plasma membrane permeability. 'Chemical ischemia' induced both an acute and a delayed time-dependent degeneration of chick retina cells. We observed that 2 min after the ischemic insult, the levels of ATP were reduced to a minimum. On the other hand, the metabolic inhibition induced the release of aspartate, glutamate and gamma-aminobutyric acid, and the activation of AMPA/kainate receptors during the period of metabolic arrest was partially responsible for the loss of mitochondrial function. However, the NMDA and non-NMDA receptor antagonists (MK-801 and CNQX) did not prevent the plasma membrane damage caused by sodium cyanide and iodoacetic acid. The results show that the collapse of the energy levels, rather than the increase in excitatory amino acids, appears to underlie the observed cell injury, suggesting an important relationship between ischemia-induced depletion of high-energy metabolites and retina cell degeneration.
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PMID:'Chemical ischemia' in cultured retina cells: the role of excitatory amino acid receptors and of energy levels on cell death. 936 12

Slices of somatosensory cortex taken from immature rats on postnatal day (P)7-14 were labeled with fura-2. Intracellular Ca2+ concentration ([Ca2+]i) was monitored in identified pyramidal cells as the ratio of fluorescence intensities (RF340/F380) during oxygen-glucose deprivation. The RF340/F380 ([Ca2+]i) of individual pyramidal cells was monitored in each of the cortical layers II-VI simultaneously. Neurons in all neocortical layers exhibited significant increases in [Ca2+]i that varied with the duration of oxygen-glucose deprivation. Individual neurons responded to oxygen-glucose deprivation with abrupt increases in [Ca2+]i after various latencies. The ceiling level of the [Ca2+]i increase differed from cell to cell. Neurons in layer II/III showed significantly greater increases in [Ca2+]i than those in layers IV, V, or VI. Kynurenic acid, a nonselective glutamate receptor antagonist, and bicuculline, a selective gamma-aminobutyric acid (GABA)A receptor antagonist, suppressed the intracellular Ca2+ accumulation induced by oxygen-glucose deprivation in all neocortical layers examined. After kynurenic acid, but not after bicuculline, there was no longer a differential [Ca2+]i increases in layer II/III. Both 2-amino-5-phosphonopentanoic acid (AP5), a selective N-methyl-D-aspartate (NMDA) receptor antagonist, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist, strongly suppressed the intracellular Ca2+ accumulation induced by oxygen-glucose deprivation in all layers. The laminar difference in terms of the [Ca2+]i increases was abolished by AP5, but not by CNQX. These results indicate that layer II/III cells are the most prone to oxygen-glucose deprivation-induced intracellular Ca2+ accumulation, and that this is primarily mediated by NMDA receptors. Thus, layer II/III neurons would be more likely to suffer cellular Ca2+ overload and excitotoxicity during ischemia than layer IV-VI cells. Such a differential laminar vulnerability might play an important role in determining the pathological characteristics of the immature cortex and its sequelae later in life.
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PMID:NMDA receptor-mediated differential laminar susceptibility to the intracellular Ca2+ accumulation induced by oxygen-glucose deprivation in rat neocortical slices. 942 11

White matter of the brain and spinal cord is susceptible to anoxia and ischemia. Irreversible injury to this tissue can have serious consequences for the overall function of the CNS through disruption of signal transmission. Myelinated axons of the CNS are critically dependent on a continuous supply of energy largely generated through oxidative phosphorylation. Anoxia and ischemia cause rapid energy depletion, failure of the Na(+)-K(+)-ATPase, and accumulation of axoplasmic Na+ through noninactivating Na+ channels, with concentrations approaching 100 mmol/L after 60 minutes of anoxia. Coupled with severe K+ depletion that results in large membrane depolarization, high [Na+]i stimulates reverse Na(+)-Ca2+ exchange and axonal Ca2+ overload. A component of Ca2+ entry occurs directly through Na+ channels. The excessive accumulation of Ca2+ in turn activates various Ca(2+)-dependent enzymes, such as calpain, phospholipases, and protein kinase C, resulting in irreversible injury. The latter enzyme may be involved in "autoprotection," triggered by release of endogenous gamma-aminobutyric acid and adenosine, by modulation of certain elements responsible for deregulation of ion homeostasis. Glycolytic block, in contrast to anoxia alone, appears to preferentially mobilize internal Ca2+ stores; as control of internal Ca2+ pools is lost, excessive release from this compartment may itself contribute to axonal damage. Reoxygenation paradoxically accelerates injury in many axons, possibly as a result of severe mitochondrial Ca2+ overload leading to a secondary failure of respiration. Although glia are relatively resistant to anoxia, oligodendrocytes and the myelin sheath may be damaged by glutamate released by reverse Na(+)-glutamate transport. Use-dependent Na+ channel blockers, particularly charged compounds such as QX-314, are highly neuroprotective in vitro, but only agents that exist partially in a neutral form, such as mexiletine and tocainide, are effective after systemic administration, because charged species cannot penetrate the blood-brain barrier easily. These concepts may also apply to other white matter disorders, such as spinal cord injury or diffuse axonal injury in brain trauma. Moreover, whereas many events are unique to white matter injury, a number of steps are common to both gray and white matter anoxia and ischemia. Optimal protection of the CNS as a whole will therefore require combination therapy aimed at unique steps in gray and white matter regions, or intervention at common points in the injury cascades.
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PMID:Anoxic and ischemic injury of myelinated axons in CNS white matter: from mechanistic concepts to therapeutics. 942 2

The septo-hippocampal pathway contains a major gamma-aminobutyric acid (GABA) projection to dendritic fields within the hippocampus. To determine the importance of the septo-hippocampal pathway in ischemia-induced accumulation of GABA and subsequent cell death in area CA1 of hippocampus, septo-hippocampal deafferentation of adult gerbils was performed. Electrolytic lesions were produced in the medial or medial plus lateral septal regions in gerbils 7 days prior to being subjected to 5 min forebrain ischemia. The extent of deafferentation of the dorsal hippocampus was determined histochemically by acetylcholinesterase staining. Both the medial and medial plus lateral septal lesions produced nearly complete loss of acetylcholinesterase staining in the dorsal hippocampus indicating relatively complete deafferentation. During and following ischemia, in vivo microdialysis was used to measure extracellular GABA accumulation, which reached concentrations up to 1060 +/- 143% of basal. Septo-hippocampal deafferentation in both groups of lesioned animals failed to prevent the accumulation of GABA (and glutamate) induced by ischemia, indicating that ischemia-induced GABA accumulation in area CA1 arises principally from intrinsic GABAergic interneurons. Ischemic animals with medial septal lesions did not demonstrate neuroprotection or increased damage in the stratum pyramidale 7 days after reperfusion. Since the septo-hippocampal pathway provides the source of GABAergic disinhibition within the hippocampus, neither disinhibition nor the septo-hippocampal input appear to play an important role in the development of ischemia-induced neuronal death in the hippocampus.
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PMID:Ischemic injury and extracellular amino acid accumulation in hippocampal area CA1 are not dependent upon an intact septo-hippocampal pathway. 951 50

The role of protein kinase C (PKC) in mediating the ischemia-induced release of amino acids in the striatum was studied using an in vivo brain dialysis technique in the striatum of spontaneously hypertensive rats (SHRs). Using HPLC combined with fluorescence detection methods, we investigated the concentrations of amino acids in the dialysates produced by 20 min of transient forebrain ischemia. We studied the effects of an inhibitor of PKC, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7) and another isoquinoline analog (HA1004) with less inhibitory effect on the C kinase in ischemia-induced amino acids release. Bilateral carotid artery occlusion caused a marked reduction in the striatal blood flow by 91 +/- 6%. The extent of the cerebral blood flow (CBF) reduction were essentially the same among H7-, HA1004-, and the vehicle-treated groups. Forebrain ischemia produced a marked increase in glutamate (21-fold of the basal concentration), aspartate (19-fold) and taurine (16-fold). Pretreatment with H7 markedly attenuated the ischemia-in-duced release of these three amino acids to 3, 3 and 4-fold of the basal values, respectively. Increase of gamma-aminobutyric acid (GABA) was also attenuated by H7 (vehicle; 2.46 +/- 1.26 microM, H7; 0.62 +/- 0.75 mM). HA1004 did not affect the release of glutamate, aspartate or GABA during ischemia. The ischemia-induced release of taurine was significantly inhibited by HA1004 but the effect was much smaller than that of H7. These results thus indicate that PKC plays a major role in the ischemia-induced release of amino acids in the striatum of SHR.
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PMID:Protein kinase C modulates ischemia-induced amino acids release in the striatum of hypertensive rats. 951 75

The manner in which arachidonic acid and other free fatty acids influence the vesicular uptake of glutamate and gamma-aminobutyric acid (GABA) has been investigated. The cis-polyunsaturated fatty acid arachidonic acid (20:4), eicosapentanoic acid (20:5) and linolenic acid (18:3) at 150 nmol/mg protein (50 microM) inhibited the vesicular uptake of glutamate and GABA more than 70%. Reduced inhibition of vesicular uptake was seen with the cis-monounsaturated fatty acid oleic acid (18:1) and the trans-mono-unsaturated fatty acid elaidic acid (18:1). The saturated fatty acids stearic acid (16:0) and arachidic acid (20:0) had no significant effect on the uptake. The inhibition of vesicular uptake by arachidonic acid was prevented by the addition of fatty acid free bovine serum albumin. Arachidonic acid inhibited in a dose-dependent manner the generation of the transmembrane pH gradient of the synaptic vesicles. This inhibition was proportional to the inhibition of the vesicular uptake of glutamate and GABA. The saturated fatty acid arachidic acid showed no inhibition of delta pH generation. Arachidonic acid at 200 nmol/mg of protein did not increase the uptake-independent leakage of glutamate and GABA from the vesicles, showing that the effect of arachidonic acid is not caused by an unspecific detergent effect. These results suggest that arachidonic acid and other polyunsaturated fatty acids are acting like proton-ionophores on the vesicular uptake of these neurotransmitters. This finding may have implications for the increased fatty acid concentration during pathological conditions like ischemia and in long term potentiation.
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PMID:The effect of arachidonic acid and free fatty acids on vesicular uptake of glutamate and gamma-aminobutyric acid. 954 50

The cell volume is regulated not only by inorganic ions, but also by organic osmolytes, such as amino acids, methylamines, and polyhydric alcohols (polyols). Using proton nuclear magnetic resonance spectroscopy (1H-NMR), we measured the tissue concentrations of amino acids (alanine, aspartate, gamma-aminobutyric acid (GABA), glutamate, glutamine, N-acetyl-aspartate (NAA), taurine), methylamines (glycerophosphorylcholine (GPC), creatine+phosphocreatine (total creatine, tCr)), and polyols (myo-inositol) in the rat brain after middle cerebral artery occlusion (incomplete focal ischemia) or after decapitation (complete global ischemia). The total osmolytes expressed as a sum of total amino acids, total methylamines, and total polyols were significantly decreased at 24 h of focal ischemia (58.7% of control value, P=0.0025) whereas they were not changed following decapitation. The water content was increased from control value of 77.9%-84.1% after focal ischemia (P<0.0001) but not after decapitation. These results suggest that the brain organic osmolytes are involved in the process of edema formation following focal cerebral ischemia. Further elucidation of the cellular mechanisms regulating these organic osmolytes in cerebral ischemia may promote greater understanding of the pathophysiology involved in the evolution of brain edema.
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PMID:Changes in brain organic osmolytes in experimental cerebral ischemia. 960 Jun 73

Because topiramate (TPM) suppresses voltage-sensitive Na+ channels and non-N-methyl-D-aspartate (NMDA) receptors and enhances gamma-aminobutyric acid (GABA)-mediated inhibition, we tested whether it would protect against cerebral ischemia. The right middle cerebral artery (MCA) was embolized by an intra-arterial injection of autogenous thrombus. Two hours after thrombus injection, animals received intra-peritoneal injections (i.p.) of normal saline as control (n=6) or alternatively, a low- (20 mg/kg, i.p., n=6) or high-dose (40 mg/kg, i.p., n=6) of TPM. Neurological deficit was scored at 2 h and 24 h following the ischemic insult. The animals were sacrificed 24 h after ischemia and the coronal brain sections were stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC) for determination of the percentage of infarct volume. Administration of TPM significantly improved the 24-h neurological deficit scores (low dose, 1.75+/-0.5; high dose, 1.17+/-0.41; p<0.05 for both doses). A reduction in the percentage of infarct volume (low dose, 22.9+/-8.9%, p=0.002; high dose 7.6+/-3.4%, p<0.001) was seen when compared to the controls (infarct size, 54.2+/-9.0%; neurobehavior score, 2. 67+/-0.52). Treatment with TPM at the higher dose induced more neuroprotection than that at the lower dose (p<0.05). Thus, treatment with TPM resulted in a dose- and use-dependent neuroprotective effect, when used 2 h after MCA embolization in a rat model of focal ischemia.
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PMID:Neuroprotection by delayed administration of topiramate in a rat model of middle cerebral artery embolization. 975 28

Adenosine has been reported to have beneficial effects against ischemic brain damage, although the mechanisms are not fully clarified. To examine the role of adenosine on the ischemia-evoked release of neurotransmitters, we applied a highly selective agonist for adenosine A1 receptor, 2-chloro-N6-cyclopentyladenosine (CCPA), into the ischemic brain using in vivo brain dialysis, which directly delivered the agonist to the local brain area. Concentrations of extracellular amino acids (glutamate, aspartate, gamma-aminobutyric acid (GABA) and taurine) and regional blood flow in the striatum of spontaneously hypertensive rats (SHRs) were monitored during cerebral ischemia elicited by bilateral carotid artery occlusion for 40 min and recirculation. Striatal blood flow and basal levels of amino acids were not affected by direct perfusion of CCPA (10 microM or 100 microM). During ischemia, concentrations of glutamate, aspartate, GABA and taurine increased up to 37-, 30-, 96- and 31-fold, respectively, when vehicle alone was administered. Administration of CCPA did not affect the changes in regional blood flow during ischemia and reperfusion. Perfusion of CCPA (100 microM), however, significantly attenuated the ischemia-evoked release of aspartate (by 70%) and glutamate (by 73%). The ischemia-induced increase of GABA tended to be decreased by CCPA, although it was not statistically significant. In contrast, both low and high concentrations of CCPA had little effect on the release of taurine during ischemia. These results suggest that stimulation of adenosine A1 receptors selectively attenuated the ischemia-evoked release of excitatory amino acids, but not of inhibitory amino acids without affecting blood flow. This modulation of the release of amino acids by adenosine A1 receptor agonists may play a protective role against ischemic neuronal damage.
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PMID:Modulation of ischemia-evoked release of excitatory and inhibitory amino acids by adenosine A1 receptor agonist. 979 30

The effect of the selective Na+/H+ antiporter inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) on amino acid release from the ischemic/reperfused rat cerebral cortex was investigated using a cortical cup technique. EIPA (25 microM in artificial cerebrospinal fluid), applied topically, inhibited the ischemia-reperfusion evoked efflux of aspartate, glutamate, gamma-aminobutyric acid, taurine and phosphoethanolamine. Reductions in the ischemia-evoked releases of these amino acids suggest that ischemia precipitates acidosis, Na+/H+ exchange and cell swelling with amino acid release as the cells mount a regulatory volume decrease response. EIPA, by blocking Na+/H+ exchange, would reduce cell swelling and the resulting amino acid release.
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PMID:5-(N-Ethyl-N-isopropyl)-amiloride inhibits amino acid release from the ischemic rat cerebral cortex: role of Na+-H+ exchange. 981 78


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