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

Nitric oxide synthase-containing neurons are presumed to be resistant to neurodegeneration and neurotoxicity, however this resistance has not been demonstrated after focal cerebral ischemia. We therefore measured the temporal profile of neuronal nitric oxide synthase (NOS-I) mRNA and immunoreactivity and NADPH-diaphorase reactivity over a one week period after permanent middle cerebral artery (MCA) occlusion in 48 male Wistar rats and compared these data to ischemic cell damage as evaluated on hematoxylin and eosin (H & E) stained sections by light microscopy. NOS-I mRNA increased as early as 15 min after MCA occlusion in the ipsilateral striatum and maximal expression of NOS-I was found in the ipsilateral cortex and striatum 1 h after MCA occlusion. The numbers of NOS-I-containing neurons in the ipsilateral cortex and striatum were significantly greater (P < 0.05) than NOS-I-containing neurons in the contralateral hemisphere at 2-48 h after the onset of ischemia. The number of NOS-I-containing neurons peaked at 4 h after MCA occlusion. Neurons exhibited shrinkage or were swollen at 1 to 4 h after MCA occlusion. At 24-48 h after ischemia, neurons in the ischemic lesion appeared to be eosinophilic or ghost like on H & E stained sections. However, some of these neurons retained morphological integrity on the NOS-I immunohistochemical sections. At 168 h after ischemia, all neurons within the lesion appeared necrotic on H & E stained sections; however, scatterred neurons expressed NOS-I and NADPH-diaphorase. The rapid upregulation of NOS-I and mRNA in the ischemic lesion suggests that NOS-I is involved in focal cerebral ischemic injury; the expression of NOS-I by neurons that retain their morphological structure in the area of the infarct suggests that NOS-I-containing neurons are more resistant to the ischemic insult. Our data also indicate a close association of NOS-I immunoreactivity and NADPH-diaphorase reactivity in ischemic brain.
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PMID:Upregulation of neuronal nitric oxide synthase and mRNA, and selective sparing of nitric oxide synthase-containing neurons after focal cerebral ischemia in rat. 752 66

The vulnerability of the developing CNS to hypoxia-ischemia (H-I) differs from that of the mature brain and is due in part to release of nitric oxide (NO) from parenchymal neurons. If NO is important in the generation of excitotoxic injury after H-I in the developing CNS, then selective destruction of the neuronal nitric oxide synthase (nNOS) cells before H-I should lessen the injury seen after the insult. Using low dose quisqualic acid (QA) injected into neonatal (postnatal d 7) parietal cortex, the nNOS neurons were eliminated while sparing other neuronal and glial populations as ascertained by NADPH diaphorase histochemistry, nNOS immunocytochemistry, and Nissl counterstain. Animals subjected to focal ischemia followed by global hypoxia 24 h after the intracortical injection of QA had more viable cortex remaining than vehicle-injected animals (83.4 +/- 4.3% versus 62.7 +/- 8.3%) and lower injury severity represented by less neuronal loss and gliosis. Intracortical injections of QA without H-I resulted in minimal cell loss at the injection site with elimination of nNOS neurons throughout the parietal cortex. Microglial and astrocytic proliferation was seen in areas damaged by H-I 3 wk after injury and clearly marked infarcted areas. Prevention or elimination of NO production from nNOS cells can prevent much of the delayed neuronal necrosis seen after H-I in the developing CNS.
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PMID:Selective destruction of nitric oxide synthase neurons with quisqualate reduces damage after hypoxia-ischemia in the neonatal rat. 861 93

To address the importance of nitric oxide or its reaction products as mediators of neurotoxicity in brain, tissue injury was assessed after transient global ischemia in mice rendered mutant in the gene for neuronal nitric oxide synthase. Halothane-anesthetized wild type and mutant mice were subjected to temporary occlusion of the basilar plus both carotid arteries for 5 or 10 min followed by three days of reperfusion. Hippocampal injury, assessed both by qualitative grading and by cell counting in the CA1 subregion, was significantly less in the mutant mice group after 5 or 10 min of ischemia. Mutant mice exhibited a lower mortality (P < 0.01), less weight loss, more normal grooming and spontaneous motor activity and better grasping in the 10 min group. There were no obvious differences in cerebrovascular anatomy or hemodynamics between wild type and mutant mice. The data suggest that a deficiency of neuronal nitric oxide synthase confers increased resistance to transient global cerebral ischemia, and support the suggestion that selective neuronal nitric oxide synthase inhibitors might reduce tissue injury associated with global cerebral ischemia.
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PMID:Attenuated hippocampal damage after global cerebral ischemia in mice mutant in neuronal nitric oxide synthase. 873 5

L-glutamate itself and compounds activating glutamate receptor subtypes such as N-methyl-D-aspartate (NMDA) can produce excitotoxic lesions similar to neuronal cell damage following ischemia, traumatic brain injury or as seen in human neurodegenerative disorders. Competitive and non-competitive NMDA-receptor antagonists have neuroprotective properties in a number of in-vitro and in-vivo models for these disorders. The discovery of nitric oxide (NO) in the central nervous system (CNS) and the demonstration of the link between glutamate receptor activation and NO formation led to the hypothesis that NMDA toxicity may be mediated by NO because of its ability to promote free radical generation. Three isoforms of nitric oxide synthase (NOS) have been described, one of which is expressed constitutively in neuronal tissues (nNOS) and is perferentially inhibited by 7-nitroindazole (7-NI). One day after intrastriatal injection of NMDA, systemic pretreatment of rats with 7-NI had no effect on lesion volumes. It is concluded that formation of NO subsequent to NMDA receptor stimulation is not critically involved in excitotoxicity seen in this model.
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PMID:NMDA-mediated toxicity to striatal neurons is not reversed by 7-nitroindazole, an inhibitor of neuronal nitric oxide synthase. 882 Oct 44

The distributions and inductions of Cu/Zn superoxide dismutase (SOD), neuronal and endothelial nitric oxide (NO) synthase (nNOS and eNOS), and nitrotyrosine (NT) were immunohistochemically examined in rabbit spinal cords after 5 and 15 min of transient ischemia. The neurons in the anterior horns (AH) were selectively lost 7 days after 15-min ischemia as compared with those of sham-operated controls. In the normal spinal cords, a number of neurons in the AHs were positive for the nNOS, and only slightly positive for the Cu/Zn SOD and the eNOS. Immunoreactivities for the proteins were induced at 8-24 h both after 5- and 15-min ischemia. In contrast, NT-like immunoreactivity was negative both in the normal and postischemic spinal cords. These results suggest that Cu/Zn SOD- and nNOS-, and eNOS-like immunoreactivities are induced, but that, even though an interaction of Cu/Zn SOD with NO could be present, NT was not detected in the motor neurons in the rabbit spinal cords after transient ischemia. Other factors could be required for NT formation found in degenerative motor neuron death in humans.
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PMID:Inductions of Cu/Zn superoxide dismutase- and nitric oxide synthase-like immunoreactivities in rabbit spinal cord after transient ischemia. 889 Dec 70

Infarct volume and edema were assessed after transient focal ischemia in mice lacking neuronal nitric oxide synthase (NOS) gene expression. With use of an 8-0 coated monofilament, the middle cerebral artery (MCA) of mutant (n = 32) and wild-type mice [SV-129 (n = 31), C57Black/6 (n = 18)] were occluded for 3 h and reperfused for up to 24 h. Regional CBF (rCBF), neurological deficits, water content, and infarct volume were examined in all three strains. rCBF, blood pressure, and heart rate did not differ between groups when measured for 1 h after reperfusion. Neurological deficits were less severe in mutant mice after MCA occlusion. Brain water content at 3 h after reperfusion and infarct volume at 24 h after reperfusion were greater in wild-type mice. These data indicate that genetic deletion of neuronal NOS confers resistance to focal ischemic injury in a reperfusion model. The findings agree with previous studies showing that tissue injury is less extensive after both permanent MCA occlusion and global ischemia in mice lacking neuronal NOS gene expression. Hence, NO may play a pivotal role in the pathogenesis of ischemic brain damage.
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PMID:Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion. 896 99

Diffusion-weighted MRI at 2 T was used to monitor and assess tissue damage after permanent middle cerebral artery occlusion (MCAO) in wild-type (WT) and mice deficient in nitric oxide synthase gene expression (nNOS-). The ischemic lesion was evaluated 3 h after occlusion and subdivided into the lesion core and peri-infarct zone based on the magnitude of the apparent diffusion coefficient (ADC) change. Infarct volume, measured by using histochemical staining 24 h after MCA occlusion, correlated best with MRI infarct volume as assessed by an ADC threshold of 25% decrease from baseline at 3 h. For ADC thresholds of greater than 25% decrease, lesion size was not significantly different in nNOS- and WT mice. However, brain tissue showing ADC decreases of 10-25% was significantly smaller in the ipsilateral hemisphere of mutants (27 +/- 2% and 21 +/- 2% in WT and nNOS-, respectively; P < 0.05). These findings occurred independently of infarct volume and are consistent with a smaller peri-infarct zone in nNOS- mice. We postulate that the smaller peri-infarct zone is a reflection of less severe metabolic disturbance after ischemia in nNOS- mice, possibly related to diminished production of nitric oxide (NO) or a related product. We conclude that magnetic resonance techniques previously used to assess ischemic damage in larger animals can be extended to the mouse, raising the possibility that the molecular mechanisms leading to ischemic damage can be examined by using genetically engineered mice.
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PMID:Neuronal nitric oxide synthase mutant mice show smaller infarcts and attenuated apparent diffusion coefficient changes in the peri-infarct zone during focal cerebral ischemia. 900 Nov 39

Ischemia is one of the strongest stimuli for gene induction in the brain. More than 80 different mRNAs have been found to be induced by brain ischemia so far. Many of these genes encode protein products that are involved directly or indirectly in neuronal survival. These include genes that promote recovery by enhanced gene expression (for example, heat shock proteins or growth factors) or attempt to protect them from delayed neuronal death (for example anti-apoptosis genes). Neuronal degeneration can be promoted by induction of apoptosis genes or genes that cause a stress to the cells, such as free radical production by nNOS or iNOS. Even though so many ischemia-inducible genes have been identified, the general reduction of gene transcription and inhibition of protein translation affect neuronal survival the most. The lack of protein synthesis is especially significant when the cells are challenged by ischemia followed by the attack of free radicals during the subsequent recirculation. Even though the ischemia-induced gene expression has a dichotomy to beneficial and harmful genes, several genes such as those encoding transcription factors may participate in both cellular responses. Therefore, pinpointing the receptors and signal transduction mechanisms responsible for the induction of different genes is of interest. So far, only NMDA (Fig. 1) and possibly KA/ AMPA receptor and to some extent alpha 2-adrenoreceptor have proved to be involved in the regulation of perifocal gene induction. Nevertheless, interfering with gene expression offers a potential opportunity for the development of a novel stroke therapy.
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PMID:Altered gene expression in brain ischemia. 908 Apr 12

We hypothesized that elimination of neuronal nitric oxide synthase (nNOS) by targeted disruption of the nNOS gene would result in amelioration of damage seen after hypoxia-ischemia in the developing brain since nitric oxide (NO) has been implicated in glutamate-mediated neurotoxicity after ischemia. Both wildtype and nNOS-deficient pups were subjected to focal ischemia followed by 1.5 h of hypoxia at Postnatal Day 7. Seven days later, brains of surviving animals were analyzed for damage. The nNOS-deficient pups (n = 17) had less histopathologic evidence of injury in both the hippocampus (P = 0.008) and the cortex (P = 0.0008) than the wildtype (n = 30) mice. When injured, the nNOS-deficient mice had damage that was limited to the hippocampus. These results support a role for neuronally produced NO in injury after perinatal hypoxia-ischemia.
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PMID:Neonatal mice lacking neuronal nitric oxide synthase are less vulnerable to hypoxic-ischemic injury. 917 13

Hypoxia-ischemia damages selected regions of the immature at different ages. Prior to 32 weeks gestation the periventricular white matter is selectively vulnerable but in the last trimester the basal ganglia become especially vulnerable to injury. Hypoxia-ischemia causes injury by activating a series of biochemical events that unfolds over a period of hours to days following the initial insult and we are investigating the ways in which age modifies these events. The cascade includes release of glutamate, overstimulation of excitatory amino acid receptors and raised intracellular levels of calcium. Clinically this series is manifested by hypoxic-ischemic encephalopathy (HIE), a syndrome that includes coma, seizures, a burst suppression EEG, respiratory depression and severe hypotonia. Clinical studies have established a relationship between the severity of neonatal encephalopathy and later manifestations of brain damage or cerebral palsy. Potential neuroprotective therapies need to be effective when given after the insult but the 'therapeutic time window' for most N-methyl-D-aspartate (NMDA) glutamate antagonists is limited after injury. Using a model of hypoxic-ischemic injury and neonatal rats and hypothermic-circulatory arrest in dogs, we found that immunohistochemical staining for neuronal nitric oxide synthase (nNOS) is markedly increased from 6 to 24 h after the insult in the basal ganglia and cortex. The induction of nNOS preceded the time of maximal neuronal necrosis and during the time when many apoptotic nuclei were appearing. We have also found that a brief period of 2 h of mild hypothermia (32 degrees C) following hypoxia-ischemia in neonatal rats delayed neuronal necrosis by more than a week. We are determining whether this delay is related to a change in nNOS activation. Induction of nNOS in the post-insult period may contribute to expression of injury and signs of encephalopathy following a hypoxic-ischemic insult.
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PMID:Hypoxic and ischemic disorders of infants and children. Lecture for 38th meeting of Japanese Society of Child Neurology, Tokyo, Japan, July 1996. 918 71


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