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)

With use of iron histochemistry and immunohistochemistry, regional changes in the appearance of iron, ferritin, transferrin, glial fibrillary acidic protein-positive astrocytes, and activated microglia were examined from 1 to 24 weeks after transient forebrain ischemia (four-vessel occlusion model) in rat brain. Expression of the C3bi receptor and the major histocompatibility complex class II antigen was used to identify microglia. Neuronal death was confirmed by hematoxylin-eosin staining only in pyramidal cells of the hippocampal CA1 region, which is known as the area most vulnerable to ischemia. Perls' reaction with 3,3'-diaminobenzidine intensification revealed iron deposits in the CA1 region after week 4, which gradually increased and formed clusters by week 24. Iron also deposited in layers III-V of the parietal cortex after week 8 and gradually built up as granular deposits in the cytoplasm of pyramidal cells in frontocortical layer V. An increasing astroglial reaction and the appearance of ferritin-immunopositive microglia paralleled the iron accumulation in the hippocampal CA1 region, indicating that iron deposition was probably produced in the process of gliosis. Neither neuronal death nor atrophy was found in the cerebral cortex. Nevertheless, an astroglial and ferritin-immunopositive microglial reaction became evident at week 8 in the parietal cortex. On the other hand, the granular iron deposition in the pyramidal neurons of frontocortical layer V was not accompanied by any glial reaction in the chronic stage of ischemia. Three different types of iron deposition in the chronic phase after transient forebrain ischemia were shown in this study. In view of the neuronal damage caused by iron-catalyzed free radical formation, the late-onset iron deposition may be relevant to the pathogenesis of the chronic brain dysfunction seen at a late stage after cerebral ischemia.
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PMID:Regional differences in late-onset iron deposition, ferritin, transferrin, astrocyte proliferation, and microglial activation after transient forebrain ischemia in rat brain. 786 Jun 55

The middle cerebral artery (mca) was intraluminally occluded for one hour prior to reperfusion in the rat. Neuronal damage as well as motor imbalance were assessed in both acute and chronic stages with or without neural transplant in the striatum. In acute stage, argyrophil III staining demonstrated "collapsed" dark neurons in the ipsilateral striatum, cortex, reticular thalamus, amygdala and sometimes in the hippocampus. They had shrunken somata and corkscrew-like dendrites. In accordance with the appearance of dark neurons, the immunoreactivity for calpain of endogenous inactive form decreased or disappeared in ischemic areas. In chronic stage, ischemic core area (striatum and cortex) got into porencephaly, and animals made rotations following methamphetamine injection. Neural transplant (fetal striatal cells) was made during 2 to 4 weeks after the ischemia. Once the transplant survived and grew in the striatum, the methamphetamine rotations were attenuated. Using mca ischemic model rats we report here pathophysiological processes that lead to neuronal damage and infarct. Neural transplants into these animals brought partial restoration in motor disturbance, offering a valuable information concerning therapeutic possibility.
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PMID:Neuronal damage following transient cerebral ischemia and its restoration by neural transplant. 788 1

The effect of (S)alpha-fluoromethylhistidine (FMH), a specific inhibitor of histamine synthesis from histidine, on ischemic damage was examined in gerbil brain after forebrain ischemia. Two h after subcutaneous FMH injection, the histamine content of the brain was significantly reduced. Neuronal loss in the CA2 region of the hippocampus 7 days after 3 min ischemia was enhanced by treatment with FMH. These results indicate that depletion of brain histamine aggravates neuronal death of hippocampal CA2 neurons after 3 min ischemia.
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PMID:Histamine depletion in brain caused by treatment with (S)alpha-fluoromethylhistidine enhances ischemic damage of gerbil hippocampal CA2 neurons. 788 40

Neuronal damage induced by ischemia involves various changes in neurotransmission. Nitric oxide (NO), a putative neurotransmitter and/or neuromodulator has some role in this neuronal damage. In the present study, the effect of NO on the terminal site of dopamine (DA) neurons in the rat striatum was examined using the microdialysis technique. First perfusion with sodium nitroprusside (SNP) as an NO donor increased extracellular DA (10 mM, 460%; 1 mM, 140%) in the striatum and decreased its metabolites. Pretreatment with tetrodotoxin (TTX, 5 microM), (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine hydrogen maleato (MK801, 1 microM) or muscimol (1 microM) inhibited SNP-induced increases in extracellular DA and decreases in DOPAC (TTX, complete block; MK801, 75% inhibition; muscimol, 80% inhibition). Second, extracellular NO, DA and DOPAC were measured in the gerbil striatum following 10 minutes of forebrain ischemia produced by occluding both carotid arteries. Occlusion of the carotid arteries also caused increases in extracellular NO and DA in the gerbil striatum (NO, 3000%; DA, 2800%). These findings suggest that NO-facilitated DA release occurs via interaction between glutamatergic and dopaminergic neurons. These changes are probably partially involved in the neurodegenerative phenomena following ischemia. It is also shown that simultaneous measurements of NO and DA using this technique may be useful in assessing ischemic changes in vivo.
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PMID:[Effect of nitric oxide on central dopaminergic neurons]. 789 32

Dopaminergic (DAergic) influence on ischemic neuronal cell damage in the dorsolateral striatum was studied. Intact and 6-hydroxydopamine (6-OHDA) lesioned rats, with and without pretreatment by D1 and D2 DA antagonists, were subjected to 20 min forebrain ischemia. Extracellular DA and glutamate (Glu) were measured using microdialysis technique. Histological examination was performed on the dorsolateral striatum and the hippocampal CA1 area 24 h after ischemia. DA increased 400-500 times the control level during ischemia among the groups except the 6-OHDA lesioned group. No significant changes were observed in the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC), but a transient decrease was seen in homovanillic acid (HVA). Due to ischemia, Glu increased up to about 5 times the control level among the groups. Neuronal damage in the dorsolateral striatum was slightly attenuated by 6-OHDA lesion. Treatment by spiperone (D2 antagonist, 7 micrograms/kg IP) alone attenuated the damage strongly. Treatment by SCH23390 (D1 antagonist, 2.5 mg/kg IP) alone or both D1 and D2 antagonists had no effects. Data suggest that excessive Glu and DA are involved in neuronal cell damage. DA might enhance the damage via D2 but inhibit via D1 receptor.
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PMID:Dopamine has inhibitory and accelerating effects on ischemia-induced neuronal cell damage in the rat striatum. 790 89

Neuronal injury following focal cerebral ischemia is widely attributed to the excitotoxic effects of glutamate. However, critical analysis of published data on glutamate toxicity in vitro and the comparison of these data with in vivo release of glutamate and the therapeutic effect of glutamate antagonists raises doubts about a neurotoxic mechanism. An alternative explanation for glutamate-mediated injury is hypoxia due to peri-infarct spreading depression-like depolarizations. These depolarizations are triggered in the core of the ischemic infarct and spread at irregular intervals into the peri-infarct surrounding. In ischemically uncompromised tissue, the metabolic workload associated with spreading depression is coupled to an increase in blood flow and oxygen supply, assuring maintenance of oxidative respiration. In the penumbra region of focal ischemia, the hemodynamic constraints of collateral blood circulation prevail the adequate adjustment of oxygen delivery, leading to transient episodes of relative tissue hypoxia. The hypoxic episodes cause a suppression of protein synthesis, a gradual deterioration of energy metabolism and a progression of irreversibly damaged tissue into the penumbra zone. The generation of peri-infarct spreading depressions and the associated metabolic workload can be suppressed by NMDA and non-NMDA antagonists. As a result, the penumbral inhibition of protein synthesis and the progressing energy failure is also prevented, and the volume of ischemic infarct decreases. Interventions to improve ischemic resistance should therefore aim at improving the oxygen supply or reducing the metabolic workload in the penumbra region.
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PMID:Glutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised. 791 80

Repeated ischemic insults at one hour intervals result in more severe neuronal damage than a single similar duration insult. The mechanism for the more severe damage with repetitive ischemia is not fully understood. We hypothesized that the prolonged reperfusion periods between the relatively short ischemic insults may result in a pronounced generation of oxygen free radicals (OFRs). In this study, we tested the protective effects of superoxide dismutase (SOD) and catalase (alone or in combination), and U78517F in a gerbil model of repetitive ischemia. Three episodes (two min each) of bilateral carotid occlusion were used at one hour intervals to produce repetitive ischemia. Superoxide dismutase and catalase were infused via osmotic pumps into the lateral ventricles. Two doses of U78517F were given three times per animal, one half hour prior to each occlusion. Neuronal damage was assessed 7 days later in several brain regions using the silver staining technique. The Mann-Whitney U test was used for statistical comparison. Superoxide dismutase showed significant protection in the hippocampus (CA4), striatum, thalamus and the medial geniculate nucleus (MGN). Catalase showed significant protection in the striatum, hippocampus, thalamus, and MGN and the substantia nigra reticulata. Combination of the two resulted in additional protection in the cerebral cortex. Compared to the controls, there was little protection in a dose of 3 mg/kg of U78517F. There was significant protection with a dose of 10 mg/kg in the hippocampus (CA4), striatum, thalamus, medial geniculate nucleus and the substantia nigra reticulata.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Superoxide dismutase, catalase, and U78517F attenuate neuronal damage in gerbils with repeated brief ischemic insults. 806 23

Neuronal injury resulting from glutamate receptor-mediated excitotoxicity has been implicated in a wide spectrum of neurological disease states, including ischemia, central nervous system trauma, and some types of neurodegenerative diseases. Excitotoxicity may interact with other pathophysiological processes to enhance neuronal injury; for example, excess glutamate release due to free radicals generated during the immune response to infection might initiate secondary excitotoxicity, and intracellular pathways that contribute to neuronal destruction may be common to both excitotoxic and nonexcitotoxic injury processes. Defining the contribution of excitotoxicity to neuronal damage in acute zoster infection and post-herpetic neuralgia may provide one means of reducing morbidity from this often debilitating disease.
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PMID:Excitotoxicity, free radicals, and cell membrane changes. 818 90

Effects of hypoxia, substrate deprivation and simulated ischemia (combined hypoxia and substrate deprivation) on cell survival during the insult itself and during a 24 h 'recovery' period were studied in primary cultures of mouse astrocytes and in cerebral cortical neuronal-astrocytic co-cultures. Cell death was determined by release of the cytosolic high molecular enzyme lactate dehydrogenase (LDH) as well as morphologically (retention of staining with rhodamine 123 and lack of staining with propidium iodide as an indicator of live cells). Glutamate concentrations were measured in the incubation media at the end of the metabolic insults. Astrocytes were very resistant to hypoxia, but less so to simulated ischemia; under both conditions the glutamate concentrations in the media remained low. Cerebral cortical neurons were almost equally susceptible to damage by hypoxia and by simulated ischemia, although hypoxia had a faster deleterious effects on some of the neurons and simulated ischemia during a long-term insult (9 h) killed all neurons, whereas a non-negligible neuronal subpopulation survived 9 h of hypoxia. Neuronal cell death after long-term hypoxia (but not after simulated ischemia) was correlated with high concentrations of glutamate in the incubation media. After certain insults, most notably relatively short lasting simulated ischemia (3 h) in neurons (which caused no increased cell death during the insult), there was a large release of LDH during the 'recovery' period.
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PMID:Cell death in primary cultures of mouse neurons and astrocytes during exposure to and 'recovery' from hypoxia, substrate deprivation and simulated ischemia. 819 61

Multiple processes lead to neuronal death after ischemia, but the generation of nitric oxide (NO) is a key component in this cascade of events. The mechanisms that regulate the extent of neuronal degeneration during anoxia and NO toxicity are multifactorial. Neuronal death may be modulated by the activity of signal transduction systems that influence the toxicity of NO or its metabolic products such as cGMP. The enzyme responsible for the production of NO, nitric oxide synthase (NOS), is phosphorylated by protein kinase C (PKC), the cAMP-dependent protein kinase (PKA), and the calcium/calmodulin-dependent protein kinase II (CaM-II). We examined in primary cultured hippocampal neurons whether the protein kinases PKC, PKA, CaM-II, and cGMP-dependent protein kinase modified the toxic effects of anoxia and NO. Down-regulation of PKC activity with PMA (1 microM) increased hippocampal neuronal survival during anoxia and NO exposure from approximately 22% to 88%. Inhibitors of PKC activity (H-7, H-8, sphingosine, and staurosporine) also were neuroprotective. Down-regulation of PKC activity increased survival during anoxia even in the presence of the NOS inhibitor, N omega-methyl-L-arginine. Thus, although down-regulation of PKC activity may increase neuronal survival by decreasing NOS activity, it also is likely that PKC contributes to ischemic neuronal death by mechanisms that are independent of NOS. Inhibition of the cGMP-dependent protein kinase activity, but not the activity of the CaM-II also was neuroprotective during NO administration. In contrast to the protective effects of inhibition of PKC and the cGMP-dependent protein kinase, activation rather than inhibition of PKA increased hippocampal neuronal survival during NO exposure. These results indicate that neuronal survival during anoxia and NO exposure is linked to the modulation of PKC, PKA, and cGMP-dependent protein kinase activity but is not dependent on the CaM-II pathway. Understanding the involvement of PKC, PKA, and the cGMP-dependent protein kinase in modulating the effect of neuronal death during ischemia and NO toxicity may help in directing future therapeutic modalities for cerebrovascular disease.
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PMID:Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia. 823 Mar 23


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