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

The expression profile of neurotrophin-3 (NT-3) mRNA in the rat hippocampus after forebrain ischemia was investigated by Northern blot and S1 nuclease protection analyses. The NT-3 transcripts in the hippocampus immediately decreased after ischemic insult, became undetectable within 3 h and remained at undetectable levels for at least 7 days. In contrast, the expression of c-fos and c-jun mRNA transiently increased both in the cerebral cortex and in the hippocampus. These results suggest that brain ischemia triggers dynamic changes in gene expression including a neurotrophic factor, which may cause functional and/or morphological changes of the neuronal network.
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PMID:Decreased expression of neurotrophin-3 mRNA in the rat hippocampus following transient forebrain ischemia. 161 77

Levels of mRNA for c-fos, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), TrkB, and TrkC were studied using in situ hybridization in the rat brain at different reperfusion times after unilateral middle cerebral artery occlusion (MCAO). Short-term (15 min) MCAO, which does not cause neuronal death, induced elevated BDNF mRNA expression confined to ipsilateral frontal and cingulate cortices outside the ischemic area. With a longer duration of MCAO (2 h), which leads to cortical infarction, the increase was more marked and elevated BDNF mRNA levels were also detected bilaterally in dentate granule cells and CA1 and CA3 pyramidal neurons. Maximum expression was found after 2 h of reperfusion. At 24 h BDNF mRNA expression had returned to control values. In the ischemic core of the parietal cortex only scattered neurons were expressing high levels of BDNF mRNA after 15 min and 2 h of MCAO. Analysis of different BDNF transcripts showed that MCAO induced a marked increase of exon III mRNA but only small increases of exon I and II mRNAs in cortex and hippocampus. In contrast to BDNF mRNA, elevated expression of c-fos mRNA was observed in the entire ipsilateral cerebral cortex, including the ischemic core, after both 15 min and 2 h of MCAO. Two hours of MCAO also induced transient, bilateral increases of NGF and TrkB mRNA levels and a decrease of NT-3 mRNA expression, confined to dentate granule cells. The upregulation of BDNF mRNA expression in cortical neurons after MCAO is probably triggered by glutamate through a spreading depression-like mechanism. The lack of response of the BDNF gene in the ischemic core may be due to suppression of signal transduction or transcription factor synthesis caused by the ischemia. The observed pattern of gene expression after MCAO agrees well with a neuroprotective role of BDNF in cortical neurons. However, elevated levels of NGF and BDNF protein could also increase synaptic efficacy in the postischemic phase, which may promote epileptogenesis.
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PMID:Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage. 758 36

Changes in nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 messenger RNA expression in the rat hippocampus following 20 min of transient forebrain ischemia were evaluated using Northern blot analysis and in situ hybridization histochemistry. Twelve hours after the insult, the level of nerve growth factor messenger RNA increased markedly in the granular cell layer of the dentate gyrus and by day 2 returned to control levels. The level of brain-derived neurotrophic factor messenger RNA showed a persistent and moderate increase. The highest expression of brain-derived neurotrophic factor messenger RNA was seen in the dentate granule cells on day 2 after the insult, and then the expression returned to the control levels. At 2 days post-ischemia, contents of messenger RNAs for nerve growth factor and brain-derived neurotrophic factor were reduced in the CA1 region, which may represent delayed loss of vulnerable CA1 pyramidal neurons. In contrast to brain-derived neurotrophic factor and nerve growth factor messenger RNA expression, the level of neurotrophin-3 messenger RNA declined in the CA1, the CA2 and the dentate granular layer immediately after ischemic insult. In the CA1 region, the reduced expression persisted for at least seven days, but in the dentate gyrus, neurotrophin-3 messenger RNA expression returned to the control levels after two days of post-ischemic recovery. These results suggest that nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 genes are differentially regulated and that each of their gene products may play different roles in the central nervous system under pathophysiological conditions.
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PMID:Coordinated expression of messenger RNAs for nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the rat hippocampus following transient forebrain ischemia. 835 Sep 88

Levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) mRNA expression were measured in a rodent model of traumatic brain injury (TBI) following unilateral injury to the cerebral cortex. To obtain reliable data on the co-expression of neurotrophin genes, adjacent coronal sections from the same rat brains were hybridized in situ with BDNF and NT3 cRNA probes. BDNF mRNA increased at 1,3, and 5 hr after unilateral cortical injury in the cortex ipsilateral to the injury site and bilaterally in the dorsal hippocampus. NT3 mRNA did not change significantly following injury. Our results suggest that TBI produces rapid increases in BDNF mRNA expression in rat brain without changes in NT3 mRNA expression, a finding which differs from studies of ischemia and seizures. It is possible that increased levels of BDNF mRNA rather than NT3 are important components of pathophysiological responses to TBI.
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PMID:Increased expression of brain-derived neurotrophic factor but not neurotrophin-3 mRNA in rat brain after cortical impact injury. 872 24

In a previous study the levels of brain-derived neurotrophic factor (BDNF) mRNA were shown to be elevated in skeletal muscle of the diabetic rat compared with age-matched control animals. It was proposed that diabetes-induced changes in nerve function may initiate changes in nerve/muscle contact akin to those following denervation of target skeletal muscle. In this study hindlimb skeletal muscles were denervated by sciatic nerve crush or transection and the effect on BDNF mRNA levels in control and diabetic rats was observed using Northern blotting. Contralateral to the side of nerve injury, the levels of BDNF mRNA in soleus muscle of diabetic rats were higher than in controls (three- to sevenfold), as has been seen previously in diabetic rats without any axotomy. Sciatic nerve crush or transection, of 1 week or of 3 weeks duration, lowered the levels of BDNF mRNA by 50% in ipsilateral soleus muscle of diabetic rats. BDNF mRNA levels in contralateral gastrocnemius muscle were not similarly raised in diabetic rats compared with controls and nerve injury had no effect. In control animals, ipsilaterally, the BDNF mRNA levels of soleus muscle were raised approximately twofold at 1 week and were lowered by approximately 50% at 3 weeks following nerve injury. Neurotrophin-3 mRNA levels were reduced approximately 50% in soleus muscle of diabetic rats compared with control rats, and nerve injury had no significant effect. The specific up-regulation of BDNF mRNA in soleus muscle of diabetic rats is discussed in terms of a proposed diabetes-induced ischemia within hindlimb skeletal muscle, with a protective role for BDNF in muscle and/or nerve being introduced.
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PMID:Brain-derived neurotrophic factor mRNA levels are up-regulated in hindlimb skeletal muscle of diabetic rats: effect of denervation. 881 63

We have investigated the neuroprotective actions of neurotrophins in a model of ischaemia using slice cultures. Ischaemia was induced in organotypic hippocampal cultures by simultaneous oxygen and glucose deprivation. Cell death was assessed 24 h later by propidium iodide fluorescence. Pre- but not post-ischaemic addition of brain-derived neurotrophic factor (BDNF) produced a concentration-dependent reduction in neuronal damage. Neurotrophin-3 was not neuroprotective. These data suggest that BDNF may form part of an endogenous neuroprotective mechanism.
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PMID:Brain-derived neurotrophic factor, but not neurotrophin-3, prevents ischaemia-induced neuronal cell death in organotypic rat hippocampal slice cultures. 881 76

The neurotrophin family of growth factors, which includes Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT3) and Neurotrophin-4/5 (NT4/5) bind and activate specific tyrosine kinase (Trk) receptors to promote cell survival and growth of different cell populations. For these reasons, growing attention has been paid to the use of neurotrophins as therapeutic agents in neurodegeneration, and to the regulation of the expression of their specific receptors by the ligands. BDNF expression, as revealed by immunohistochemistry, is found in the pre-subiculum, CA1, CA3, and dentate gyrus of the hippocampus. Strong TrkB immunoreactivity is present in most CA3 neurons but only in scattered neurons of the CA1 area. Weak TrkB immunoreactivity is found in the granule cell layer of the dentate gyrus. Unilateral grafting of BDNF-transfected fibroblasts into the hippocampus resulted in a marked increase in the intensity of the immunoreaction and in the number of TrkB-immunoreactive neurons in the granule cell layer of the dentate gyrus, pre-subiculum and CA1 area in the vicinity of the graft. No similar effects were produced after the injection of control mock-transfected fibroblasts. Delayed cell death in the CA1 area was produced following 5 min of forebrain ischemia in the gerbil. The majority of living cells in the CA1 area at the fourth day were BDNF/TrkB immunoreactive. Unilateral grafting of control mock-transfected or BDNF fibroblasts two days before ischemia resulted in a moderate non-specific protection of TrkB-negative, but not TrkB-positive cells, in the CA1 area of the grafted side. This finding is in line with a vascular and glial reaction, as revealed, by immunohistochemistry using astroglial and microglial cell markers. This astroglial response was higher in the grafted side than in the contralateral side in ischemic gerbils, but no differences were seen between BDNF-producing and non-BDNF-producing grafts. However, grafting of BDNF-producing fibroblasts two days before ischemia significantly and specifically prevented nerve cells from dying in the CA1 area of the ipsilateral hippocampus. Cell survival was associated with increased TrkB immunoreactivity as the majority of living cells were TrkB immunoreactive. Thus, our results show that BDNF is able to up-regulate the expression of TrkB in control and pathological states, and that BDNF prevention of neuronal death following transient forebrain ischemia is associated with increased expression of its specific receptor.
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PMID:BDNF up-regulates TrkB protein and prevents the death of CA1 neurons following transient forebrain ischemia. 954 84

Dexamethasone (DEX) increases the expression of neurotrophin-3 (NT-3) in normal rat hippocampal neurons, whereas transient forebrain ischemia reduces the NT-3 mRNA level. The effect of DEX on the expression of NT-3 mRNA in injured brain cells after ischemia has not been investigated, however. Using in situ hybridization and ribonuclease protection assay methods, we studied NT-3 mRNA expression in rats with and without DEX administration after transient forebrain ischemia. Without DEX treatment, NT-3 mRNA was down-regulated in the hippocampal neurons at 2, 4, 12 h and returned to basal levels 24 h following ischemia. With DEX treatment, however, NT-3 mRNA showed no change at 2, 4 and 12 h and increased 24 h after ischemia. The results indicate that DEX inhibits ischemia-induced NT-3 mRNA down-regulation during the first 12 h and up-regulates NT-3 mRNA 24 h after ischemia. DEX administration might be effective in influencing some of the pathophysiological effects of ischemia in the hippocampus.
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PMID:Dexamethasone inhibits ischemia-induced transient reduction of neurotrophin-3 mRNA in rat hippocampal neurons. 985 2

We examined the uptake and distribution of an antisense phosphorothioated oligodeoxynucleotide (s-ODN) to c-fos, rncfosr115, infused into the left cerebral ventricle of male Long-Evans rats and the effect of this s-ODN on subsequent Fos, NGF, neurotrophin-3 (NT-3), and actin expression. To establish the uptake and turnover of s-ODN in the brain, we studied the copurification of the immunoreactivity of biotin with biotinylated s-ODN that was recovered from different regions of the brain. A time-dependent diffusion and the localization of s-ODN were further demonstrated by labeling the 3'-OH terminus of s-ODN in situ with digoxigenin-dUTP using terminal transferase and detection using anti-digoxigenin IgG-FITC. Cellular uptake of the s-ODN was evident in both the hippocampal and cortical regions, consistent with a gradient originating at the ventricular surface. Degradation of the s-ODN was observed beginning 48 hr after delivery. The effectiveness of c-fos antisense s-ODN was demonstrated by its suppression of postischemic Fos expression, which was accompanied by an inhibition of ischemia-induced NGF mRNA expression in the dentate gyrus. Infusion of saline, the sense s-ODN, or a mismatch antisense s-ODN did not suppress Fos expression. That this effect of c-fos antisense s-ODN was specific to NGF was demonstrated by its lack of effect on the postischemic expression of the NT-3 and beta-actin genes. Our results demonstrate that c-fos antisense s-ODN blocks selected downstream events and support the contention that postischemic Fos regulates the subsequent expression of the NGF gene and that Fos expression may have a functional component in neuroregeneration after focal cerebral ischemia-reperfusion.
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PMID:Suppression of postischemic hippocampal nerve growth factor expression by a c-fos antisense oligodeoxynucleotide. 995 11

Some studies have provided evidence that delayed death of hippocampal CA1 neurons in transient global ischemia occurs by classical apoptosis. Recently, translocation of synaptic zinc has been shown to play a key role in ischemic CA1 neuronal death. With these two lines of evidence, we examined in mouse cortical cultures the possibility that zinc neurotoxicity, slowly triggered over a day, may occur by classical apoptosis. Exposure of cortical cultures to 30-35 microM zinc for 24 h resulted in slowly evolving death of neurons only, while exposure to zinc at higher concentrations ( > or = 40 microM) produced near-complete death of both neurons and glia. DNA agarose gel electrophoresis revealed internucleosomal DNA fragmentation, and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method revealed DNA breaks in degenerating neurons after 24 h exposure to 30-35 microM zinc, suggesting that the death may occur by apoptosis. However, electron-microscopic examinations revealed ultrastructural changes clearly indicative of necrosis, such as marked swelling of intracellular organelles and disruption of cell membranes amid relatively intact nuclear membranes. Furthermore, the slowly triggered zinc neurotoxicity was not attenuated by cycloheximide, neurotrophins (brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4/5) or high potassium, all of which effectively reduced several forms of apoptosis in our cortical cultures. Interestingly, a vitamin E analogue trolox almost completely blocked slowly triggered zinc neurotoxicity, indicating that free radical injury is the main mechanism of zinc neurotoxicity. Consistently, exposure to zinc increased membrane lipid peroxidation assessed by the thiobarbituric acid reactive substance assay. Although zinc-induced neuronal death, slowly triggered over a day, is associated with DNA fragmentation, overall it exhibited features more typical of necrosis. This neuronal death is probably mediated by free radical injury. Further studies appear warranted to investigate the mechanistic link between toxic zinc influx and free radical generation and the possibility that selective neuronal death in transient global ischemia also occurs by zinc-triggered neuronal death exhibiting features of both apoptosis and necrosis.
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PMID:Zinc-induced cortical neuronal death with features of apoptosis and necrosis: mediation by free radicals. 1005 Dec 27


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