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)

Although it is well known that brain ischemia is dominantly caused by hypoxia and hypoglycemia, it is still unclear how hypoxia participates in ischemia. We studied the changes in neuronal nitric oxide synthase (nNOS) and the effect of the NOS inhibitor NG-nitro-L-arginine (NNA) on hypoxia. In vivo hypoxia (5% O2/95% N2 for 30 min) induced mild degenerative neuronal changes (shrunken and eosinophilic somata with picnotic nuclei) in neurons of the CA3, the hilus of the dentate gyrus (DG) and the DG, but not in the CA1. At 3 and 7 days after hypoxia, levels of nNOS protein were significantly enhanced to 153 and 209%, but iNOS protein could not be detected. The numbers of nNOS-immunopositive neurons were significantly enhanced to 145 and 191% in the CA3, 145 and 178% in the hilus of the DG, and 243 and 387% in the DG after 3 and 7 days, respectively. In contrast, no statistical difference was determined in the CA1. We further examined the effect of NNA administered at 5 min and 3, 6, and 24 h after hypoxia. Administration of NNA (0.1 and 1 mg/kg, i.p.) significantly decreased the number of damaged neurons in the hilus of the DG and the DG. However, higher doses of NNA (10 mg/kg, i.p.) did not prevent damage. These results suggest that hypoxia alone induces enhancement of nNOS protein and nNOS immunoreactivity in neurons of the hippocampus and that NNA has biphasic effects against hypoxia-induced neuronal damage in the hilus of the DG and the DG.
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PMID:In vivo hypoxia-induced neuronal damage with an enhancement of neuronal nitric oxide synthase immunoreactivity in hippocampus. 922 38

In anesthetized piglets, endothelial and neuronal nitric oxide synthase (eNOS and nNOS, respectively) levels were investigated after global cerebral ischemia. Increased intracranial pressure was used to produce 5 or 10 minutes of global ischemia, which was verified visually by observing pial arteriolar blood flow and by a microsphere technique. At 4 to 6 hours of reperfusion, parietal cortex, hippocampus, and cerebellum were collected for immunohistochemical or immunoblot analysis. Immunohistochemical examination localized eNOS only to blood vessels and nNOS only to nonvascular cells, which were primarily neurons in all regions examined. Analysis of immunoblot data revealed significant increases in eNOS levels from 47 +/- 22 pixels/micrograms protein for time controls to 77 +/- 36 pixels/micrograms protein (75% increase) for ischemia in parietal cortex (n = 9 to 10) and 22 +/- 10 for control to 40 +/- 16 pixels/micrograms protein (40% increase) for ischemia in hippocampus (n = 7 to 8). Levels of eNOS in cerebellum also tended to be higher but were variable and not significant (n = 5 to 6). In contrast, changes in nNOS levels were not detected at 4 or 6 hours. The increase in eNOS levels detected on immunoblots also was apparent on tissue sections as an increase in intensity of staining. Cyclooxygenase-dependent mechanisms were investigated with respect to the ischemia-induced increase in eNOS levels. Pretreatment with the cyclooxygenase inhibitor indomethacin (5 mg/kg intravenously) abolished the ischemia-induced eNOS increase in parietal cortex and hippocampus (n = 7). Thus, we conclude that the eNOS response is rapid, specific to vessels, and involves an indomethacin-sensitive mechanism.
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PMID:Cerebral ischemia/reperfusion increases endothelial nitric oxide synthase levels by an indomethacin-sensitive mechanism. 942 9

Changes in the regional distribution of protein kinase C (PKC) after transient focal cerebral ischemia in SV-129 mice were assessed by quantitative autoradiography using [3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding. [3H]PDBu binding did not change up to 10 min after reperfusion of 3 h ischemia, but at 1 h after reperfusion markedly decreased to 40-50% of control (pre-ischemia) in the ipsilateral striatum and the middle cerebral artery (MCA) region of cortex in SV-129 mice. The binding decreased to 20% of control at 3-7 days after reperfusion, but did not change in the ipsilateral anterior cerebral artery (ACA) territory or the contralateral brain. In the ipsilateral substantia nigra, which lies outside the ischemic zone, [3H]PDBu binding was not significantly changed compared to the control values (pre-ischemia) at early phase (up to 3 h after reperfusion), but marked reduction of the binding was observed 1 day after reperfusion. After 3 h ischemia followed by 3 h reperfusion, the morphological damage and the decrease in [3H]PDBu binding in the ipsilateral striatum and the MCA region of cortex was smaller in mice lacking the expression of neuronal nitric oxide synthase (type I NOS) gene mutant mice compared to wild-type (SV-129 and C57black/6) mice. Our data suggest that postischemic alterations of PKC binding activity were observed in the ischemic and non-ischemic lesions in the mouse brain.
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PMID:Alteration of protein kinase C activity after transient focal cerebral ischemia in mice using in vitro [3H]phorbol-12,13-dibutyrate binding autoradiography. 945 94

Administration of inhibitors of neuronal nitric oxide synthase or deletion of the encoding gene in rodents provided evidence that neuronal nitric oxide synthase activity may contribute to neuronal cell death following global and focal cerebral ischemia. In the present study, we investigated by in situ hybridization the expression of an endogenous inhibitor of neuronal nitric oxide synthase activity, designated protein inhibitor of neuronal nitric oxide synthase and homologous to cytoplasmic dynein light chain, in the post-ischemic rat brain. Following global ischemia induced by cardiac arrest, messenger RNA expression of protein inhibitor of neuronal nitric oxide synthase was rapidly induced in pyramidal neurons of the hippocampal CA3 region and granule cell of the dentate gyrus which are resistant to ischemic damage. In vulnerable CA1 pyramidal neurons however, protein inhibitor of neuronal nitric oxide synthase expression remained at basal level after global ischemia and was associated with an increase in nicotinamide adenine dinucleotide phosphate-diaphorase activity and subsequent DNA fragmentation indicating ischemia-mediated neuronal cell death. Following focal cerebral ischemia induced by permanent occlusion of the middle cerebral artery, transcripts of protein inhibitor of neuronal nitric oxide synthase progressively accumulated in cortical neurons bordering the infarct area. After transient middle cerebral artery occlusion however, messenger RNA levels of protein inhibitor of neuronal nitric oxide synthase increased in the reperfused neocortex. Our findings indicate that cerebral ischemia leads to an increase in neuronal expression of protein inhibitor of neuronal nitric oxide synthase in brain regions where sustained or "uncoupled" nitric oxide synthase activity may be detrimental to neurons. Lack of post-ischemic induction of protein inhibitor of neuronal nitric oxide synthase in CA1 pyramidal neurons may result in high nitric oxide synthase activity after global ischemia and could contribute to delayed neuronal cell death.
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PMID:Induction of protein inhibitor of neuronal nitric oxide synthase/cytoplasmic dynein light chain following cerebral ischemia. 952 64

Nitric oxide (NO) plays a complex role in the pathophysiology of cerebral ischemia. In this study, mutant mice with disrupted type I (neuronal) NO synthase (nNOS) were compared with wild-type littermates after permanent focal ischemia. Cerebral blood flow in the central and peripheral zones of the ischemic distribution were measured with laser doppler flowmetry. Simultaneously, microdialysis electrodes were used to measure extracellular amino acid concentrations and DC potential in these same locations. Blood flow was reduced to <25 and 60% of baseline levels in the central and peripheral zones, respectively; there were no differences in nNOS mutants versus wild-type mice. Within the central ischemic zone, DC potentials rapidly shifted to -20 mV in all mice. In the ischemic periphery, spreading depression (SD)-like waves of depolarization were observed. SD-like events were significantly fewer in the nNOS mutant mice. Concurrent with these hemodynamic and electrophysiological perturbations, extracellular elevations in amino acids occurred after ischemia. There were no detectable differences between wild-type and mutant mice in the ischemic periphery. However, in the central zone of ischemia, elevations in glutamate and GABA were significantly lower in the nNOS mutants. Twenty-four hour infarct volumes in the nNOS mutant mice were significantly smaller than in their wild-type littermates. Overall, the number of SD-like depolarizations and the integrated efflux of glutamate were significantly correlated with infarct size. These results suggest that NO derived from the nNOS isoform contributes to tissue damage after focal ischemia by amplifying excitotoxic amino acid release in the core and deleterious waves of SD-like depolarizations in the periphery.
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PMID:Attenuated neurotransmitter release and spreading depression-like depolarizations after focal ischemia in mutant mice with disrupted type I nitric oxide synthase gene. 980 93

The effects of chronic 17beta-estradiol (E2) depletion, via ovariectomy (OVX), and its repletion, on cortical cerebral blood flow (CBF) and EEG activities during forebrain ischemia, as well as post-ischemic recovery and neuropathology, were assessed and compared with results obtained in normal female rats. We also examined whether neuronal nitric oxide synthase (nNOS) activity is affected by OVX and E2 replacement and whether NOS-derived NO supports vasodilation during ischemia. OVX females displayed a significantly lower CBF during ischemia (10% of baseline) than did normal females (23% of baseline). In OVX rats, given chronic low-dose E2 treatment (0.1 mg kg(-1) day(-1)), intra-ischemic CBF was similar to normal females (25% of baseline). However, at supraphysiologic E2 doses (> or = 0.5 mg kg(-1) day(-1)), that benefit was diminished or lost. Intra-ischemic EEG power reductions and post-ischemic survival rates, neurological dysfunction, and histopathology displayed similar relative differences among groups as the CBF findings. Intra-ischemic CBF was reduced by nNOS inhibition, with ARL 17477, in normal and low-dose E2-treated OVX rats (4-8% baseline). The repressed intra-ischemic vasodilating function in OVX rats may be due to reductions in nNOS activity, because untreated OVX rats showed a 50% lower cortical nNOS activity than that in normal rats and in rats treated with low or high dose (5 mg kg(-1) day(-1)) E2. However, the inability to restore vasodilating function despite normalization of nNOS activity indicates that another mechanism is responsible for the repression of vasodilatory function in the high-dose group. These findings suggest that E2, at levels within the physiological range, promotes ischemic neuroprotection via improving vasodilating capacity. One possible mechanism may relate to E2 enhancing brain nNOS expression and activity.
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PMID:Cerebral vasodilating capacity during forebrain ischemia: effects of chronic estrogen depletion and repletion and the role of neuronal nitric oxide synthase. 983 65

In this study, the N-Methyl-D-Aspartate (NMDA) receptor-dependent nitric oxide and cyclic GMP (cGMP) synthesis in the course of reperfusion after 5 min of ischemia in gerbil brain hemispheres and cerebellum were investigated. Moreover, the role of the neuronal isoform of nitric oxide (NO) synthase (nNOS) in liberation of NO in postischemic brain and the involvement of NO in membrane lipoperoxidations activated during reperfusion were evaluated. Enhancement of Ca2+/calmodulin-regulated NOS activity and cGMP level in brain hemispheres and in cerebellum during reperfusion was found to be coupled to the activation of the NMDA receptor. cGMP concentration 40% above the control level was observed to persist up to 7 days after ischemia. The amount of conjugated double bounds in membrane lipids and the level of thiobarbituric acid reactive substances were increased exclusively in brain hemispheres, indicating activation of lipid peroxidation. The NMDA receptor antagonist, MK-801, eliminated, and a rather selective nNOS inhibitor, 7-Nitroindazole (7-NI) attenuated, NMDA receptor-evoked enhancement of NOS activity and cGMP level in brain hemispheres and in cerebellum during reperfusion. Moreover, 7-NI decreased significantly membrane lipid peroxidation during the early time of reperfusion. Histological examination demonstrated that 7-NI protects against death a selected population of neuronal cells in CA1 layer of hippocampus. It is suggested that NMDA receptor dependence of NO release during reperfusion is responsible for the degeneration of some populations of neurons and that the effect is mediated by activation of free radical formation and lipid peroxidation. Moreover, in cerebellum, ischemia-evoked activation of glutamatergic system stimulates NO-dependent signal transmission. Our results indicated that 7-NI has a significant ameliorating effect on biochemical alterations evoked by ischemia, suggesting nNOS inhibitors as a potential therapeutic agents in reperfusion injury.
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PMID:NMDA receptor-dependent nitric oxide and cGMP synthesis in brain hemispheres and cerebellum during reperfusion after transient forebrain ischemia in gerbils: effect of 7-Nitroindazole. 984 59

The purpose of this study was to evaluate the role of neuronal nitric oxide synthase (nNOS) in nitrotyrosine (NO2-Tyr) formation in the early phase of ischemia-reperfusion in mouse brain. Using a hydrolysis/high pressure liquid chromatography (HPLC) procedure (0.6 microM detection limit), we measured %NO2-Tyr (ratio of NO2-Tyr to total tyrosine) in 23 male C57Black/6J mice subjected to 2-h middle cerebral artery occlusion followed by 0.5-h reperfusion, in the presence (25 or 50 mg/kg) and absence of 7-nitroindazole (7-NI), a relatively specific nNOS inhibitor. At 25 mg/kg, 7-NI reduced NO2-Tyr formation to about a half of that in the vehicle-treated group (0.10 +/- 0.07 vs. 0.18 +/- 0.05%), while 50 mg/kg suppressed NO2-Tyr formation to below the limit of detection, indicating that nNOS is responsible for most of the NO2-Tyr formation in the early phase after reperfusion.
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PMID:7-Nitroindazole attenuates nitrotyrosine formation in the early phase of cerebral ischemia-reperfusion in mice. 1040 91

Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.
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PMID:Nitric oxide synthases: targets for therapeutic strategies in neurological diseases. 1044 86

We investigated oxidative damage to the c-fos gene and to its transcription in the brain of Long-Evans rats using a transient focal cerebral ischemia and reperfusion (FCIR) model. We observed a significant (p < 0.001) increase in the immunoreactivity to 8-hydroxy-2'-guanine (oh8G) and its deoxy form (oh8dG) in the ischemic cortex at 0-30 min of reperfusion in all 27 animals treated with 15-90 min of ischemia. Treatment with a neuronal nitric oxide synthase (nNOS) inhibitor, 3-bromo-7-nitroindazole (60 mg/kg, i.p.), abolished the majority but not all of the oh8G/oh8dG immunoreactivity. Treatment with RNase A reduced the oh8G immunoreactivity, suggesting that RNA may be targeted. This observation was further supported by decreased levels of mRNA transcripts of the c-fos and actin genes in the ischemic core within 30 min of reperfusion using in situ hybridization. The reduction in mRNA transcription occurred at a time when nuclear gene damage, detected as sensitive sites to Escherichia coli Fpg protein in the transcribed strand of the c-fos gene, was increased 13-fold (p < 0.01). Our results suggest that inhibiting nNOS partially attenuates FCIR-induced oxidative damage and that nNOS or other mechanisms induce nuclear gene damage that interferes with gene transcription in the brain.
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PMID:Oxidative damage to the c-fos gene and reduction of its transcription after focal cerebral ischemia. 1046 8


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