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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Organotypic hippocampal slice cultures represent a feasible model for studies of cerebral ischemia and the role of ionotropic glutamate receptors in oxygen-glucose deprivation-induced neurodegeneration. New results and a review of existing data are presented in the first part of this paper. The role of glutamate transporters, with special reference to recent results on inhibition of glutamate transporters under normal and energy-failure (ischemia-like) conditions is reviewed in the last part of the paper. The experimental work is based on hippocampal slice cultures derived from 7 day old rats and grown for about 3 weeks. In such cultures we investigated the subfield neuronal susceptibility to oxygen-glucose deprivation, the type of induced cell death and the involvement of ionotropic glutamate receptors. Hippocampal slice cultures were also used in our studies on glutamate transporters reviewed in the last part of this paper. Neurodegeneration was monitored and/or shown by cellular uptake of propidium iodide, loss of immunocytochemical staining for microtubule-associated protein 2 and staining with Fluoro-Jade B. To distinguish between necrotic vs. apoptotic neuronal cell death we used immunocytochemical staining for active caspase-3 (apoptosis indicator) and Hoechst 33342 staining of nuclear chromatin. Our experimental studies on oxygen-glucose deprivation confirmed that CA1 pyramidal cells were the most susceptible to this ischemia-like condition. Judged by propidium iodide uptake, a selective CA1 lesion, with only minor affection on CA3, occurred in cultures exposed to oxygen-glucose deprivation for 30 min. Nuclear chromatin staining by Hoechst 33342 and staining for active caspase-3 showed that oxygen-glucose deprivation induced necrotic cell death only. Addition of 10 microM of the N-methyl-D-aspartate glutamate receptor antagonist MK-801, and 20 microM of the non-N-methyl-D-aspartate glutamate receptor antagonist 2,3-dihyroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline to the culture medium confirmed that both N-methyl-D-aspartate and non-N-methyl-D-aspartate ionotropic glutamate receptors were involved in the oxygen-glucose deprivation-induced cell death. Glutamate is normally quickly removed, from the extracellular space by sodium-dependent glutamate transporters. Effects of blocking the transporters by addition of the DL-threo-beta-benzyloxyaspartate are reviewed in the last part of the paper. Under normal conditions addition of DL-threo-beta-benzyloxyaspartate in concentrations of 25 microM or more to otherwise untreated hippocampal slice cultures induced neuronal cell death, which was prevented by addition of 2,3-dihyroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and MK-801. In energy failure situations, like cerebral ischemia and oxygen-glucose deprivation, the transporters are believed to reverse and release glutamate to the extracellular space. Blockade of the transporters by a subtoxic (10 microM) dose of DL-threo-beta-benzyloxyaspartate during oxygen-glucose deprivation (but not during the next 48 h after oxygen-glucose deprivation) significantly reduced the oxygen-glucose deprivation-induced propidium iodide uptake, suggesting a neuroprotective inhibition of reverse transporter activity by DL-threo-beta-benzyloxyaspartate during oxygen-glucose deprivation under these conditions. Adding to this, other results from our laboratory have demonstrated that pre-treatment of the slice cultures with glial cell-line derived neurotrophic factor upregulates glutamate transporters. As a logical, but in some glial cell-line derived neurotrophic factor therapy-related conditions clearly unwanted consequence the susceptibility for oxygen-glucose deprivation-induced glutamate receptor-mediated cell death is increased after glial cell-line derived neurotrophic factor treatment. In summary, we conclude that both ionotropic glutamate receptors and glutamate transporters are involved in oxygen-glucose deprivation-induced necrotic cell death in hippocampal slice cultures, which have proven to be a feasible tool in experimental studies on this topic.
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PMID:Ionotropic glutamate receptors and glutamate transporters are involved in necrotic neuronal cell death induced by oxygen-glucose deprivation of hippocampal slice cultures. 1634 51

In this study we examined whether expression of microtubule-associated protein 2 (MAP2) after transient global cerebral ischemia can be influenced by behavioral experience and if the changes are associated with functional improvement. Rats received either ischemia or sham surgery then assigned to: complex environment housing (EC) or social housing (SC) as controls for 14 days followed by water maze testing. Upregulation of MAP2 was seen in all ischemic animals with a significant overall increase evident in the EC housed rats. Behaviorally, all animals learned to perform the water maze task over time but the ischemia SC rats had the worst performance overall while all the EC housed animals demonstrated the best performance in general. Regression analysis showed that increase MAP2 expression was able to explain some of the variance in the behavioral parameters in the water maze suggesting that this cytoskeletal protein probably played a role in mediating enhanced functional outcomes.
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PMID:Amelioration of cognitive impairment and changes in microtubule-associated protein 2 after transient global cerebral ischemia are influenced by complex environment experience. 1635 57

Although stem cell-based treatments for stroke and other neurodegenerative diseases have advanced rapidly, there are still few clinical treatments available. In this study, rats receiving intracerebral peripheral blood hematopoietic stem cell (CD34+) (PBSC) transplantation showed much more improvement in neurological function after chronic cerebral ischemia in comparison with vehicle-treated control rats. Using laser-scanning confocal microscopy, implanted PBSCs were seen to differentiate into glial cells [GFAP+ (glial fibrillary acidic protein-positive)], neurons [Nestin+, MAP-2+ (microtubule-associated protein 2-positive), Neu-N+ (neuronal nuclear antigen-positive)], and vascular endothelial cells [vWF+ (von Willebrand factor-positive)], thereby enhancing neuroplastic effects in the ischemic brain. Cortical neuronal activity, as evaluated by 1H-MRS (proton magnetic resonance spectroscopy), also increased considerably in PBSC-treated rats compared with a vehicle-treated control group. In addition, PBSC implantation promoted the formation of new vessels, thereby increasing the local cortical blood flow in the ischemic hemisphere. These observations may be explained by the involvement of stem cell-derived macrophage/microglial cells, and beta1 integrin expression, which might enhance this angiogenic architecture over the ischemic brain. Furthermore, quantitative reverse transcription-PCR analysis showed significantly increased modulation of neurotrophic factor expression in the ischemic hemisphere of the PBSC-transplanted rats compared with vehicle-treated control rats. Thus, intracerebral PBSC transplantation might have potential as a therapeutic strategy for treating cerebrovascular diseases.
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PMID:Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. 1657 51

The aim of the study was to assess the level of calpain and its endogenous substrates--microtubule-associated protein 2 (MAP-2) and fodrin in the rodent model of global cerebral ischaemia caused by temporary cardiac arrest accurately mimics cardiac infarct and reperfusion in human. The effects of 10 min global ischaemia were measured immediately and in several post-resuscitation periods (1 h, 24 h, and 7 days). In Western blots we observed a significant, time-dependent increase in the expression of enzyme's protein. The proteolytic effect of its activity was also time-dependent and evidenced 24 h after ischaemic episode as an increased level of 150-kDa alpha-fodrin breakdown product (FBDP). Parallel to these changes, expression of MAP-2 protein was lowered. Additionally, the electron microscopic studies of synapses showed a decreased number of synaptic vesicles early after ischaemic insult. In conclusion, our results show a temporal pattern of changes in calpain proteolytic activity and protein expression in the applied model of brain ischaemia caused by cardiac arrest and reperfusion. In these conditions calpain-mediated degradation of cytoskeleton may be involved in the disturbances in synaptic vesicles transport and hence to the changes in neurotransmission.
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PMID:Changes of cytoskeletal proteins in ischaemic brain under cardiac arrest and reperfusion conditions. 1682 96

Estradiol is protective in experimental cerebral ischemia, but the precise mechanisms remain unknown. Signal transducer and activator of transcription-3 (STAT3) is a transcription factor that is activated by estrogen, translocates to the nucleus, and induces the transcription of neuroprotective genes, such as bcl-2. We determined whether estradiol increases STAT3 activation in female rat brain after focal cerebral ischemia and whether STAT3 activation contributes to estradiol-mediated neuroprotection against ischemic brain injury. Ovariectomized (OVX) female rats with and without estradiol replacement were subjected to 2 h of middle cerebral artery occlusion (MCAO), and phosphorylated STAT3 (P-STAT3) and total STAT3 (T-STAT3) were quantified by Western blot analysis at 3 and 22 h of reperfusion. STAT3 activation was colocalized with neuronal and survival markers microtubule-associated protein 2 (MAP2) and Bcl-2 using immunohistochemistry. Infarct size was measured at 22 h after MCAO in estradiol-treated OVX animals in the presence and absence of STAT3 inhibitor cucurbitacin I (JSI-124) using 2,3,5-triphenyltetrazolium chloride staining. Estradiol increased P-STAT3 in the ischemic cortex cytosolic fraction at 3 h after MCAO without affecting T-STAT3. This was associated with increased P-STAT3 in the nuclear fraction, which remained elevated at 22 h after MCAO. The nuclear P-STAT3 colocalized with MAP2 and Bcl-2 within the peri-infarct zone. The P-STAT3 inhibitor JSI-124 abolished the protective effect of estradiol without affecting infarct size in untreated OVX rats. We conclude that estradiol increases STAT3 phosphorylation in neurons after MCAO and that STAT3 activation plays an important role in estradiol-mediated neuroprotection.
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PMID:Role of signal transducer and activator of transcription-3 in estradiol-mediated neuroprotection. 1761 Dec 79

The protective action of nerve growth factor (NGF) on delayed neuronal death (DND) after transient cerebral ischaemia and on the associated decrease in microtubule-associated protein 2 (MAP2) has been investigated. Transient forebrain ischaemia was induced for different periods (2 min, 5 min, and 8 min) in male Wistar rats by transient bilateral occlusion of the common carotid arteries and by lowering the systemic blood pressure to 50 mmHg. Histological evaluation of neuronal cell death and immunoblot analysis of MAP2 were made on the first and the seventh days after ischaemia. The mean cell death on the seventh day after ischaemia was 2.0%+/-1.8% in the 2-min group (n=6), 41%+/-19% in the 5-min group (n=6), and 75%+/-20% in the 8-min group (n=6). The concentration of MAP2 in the hippocampal homogenate 24 hours after ischaemia decreased to 82%+/-9% of the control value in the 2-min group (n=6), to 65%+/-8% in the 5-min group (n=6), and to 58%+/-4% in the 8-min group (n=6), and it remained constant at these levels through the seventh day after ischaemia. The protective action of NGF against DND was studied by administering 2 mug of 2.5S NGF (NGF-treated group, n=6) or artificial cerebrospinal fluid (CSF-treated group, n=6) through an osmotic pump implanted in the lateral ventricles 48 hours before the onset of ischaemia. The mean cell death on the seventh day after ischaemia was 42%+/-31% in the CSF-treated group, and 11%+/-15% in the NGF-treated group. The concentration of MAP2 in the hippocampal homogenate on the first day after ischaemia was 75%+/-9% in the CSF-treated group, and 82%+/-6% in the NGF-treated group, and it remained at about the same levels up to the 7th day after ischaemia. These results suggest that, 1: degradation of MAP2 precedes DND, 2: the severity of the preceding decrease of MAP2 correlated well with the severity of the DND, 3: intraventricular NGF has a protective effect against DND, and 4: the effect of NGF brain injury may be mediated by the modulation of MAP2 metabolism.
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PMID:Effect of nerve growth factor on delayed neuronal death and microtubule-associated protein 2 after transient cerebral ischaemia in the rat. 1863 43

Embryonic mesenchymal stem cells (eMSCs) were first derived from human embryonic stem cells (hESCs) overexpressing green fluorescence protein (GFP). They expressed CD29, CD44, CD73, CD105, CD166 and nestin, but not CD34, CD45, CD106 SSEA-4 or Oct3/4. Twenty million eMSCs in 1 mL of phosphate-buffered saline (PBS) were injected into the femoral veins of spontaneously hypertensive rats after transient middle cerebral artery occlusion. The migration and differentiation of the eMSCs in the ischemic brain were analyzed. The results revealed that eMSCs migrated to the infarction region and differentiated into neurons, which were positive for beta-tubulin III, microtubule-associated protein 2 (MAP2), HuC, neurofilament and human nuclear antibody, and to vascular endothelial cells, which were positive for von Willebrand factor (vWF). The transplanted cells survived in the infarction region for at least 4 weeks. Adhesive removal function significantly improved in the first week after cell transplantation, and rotarod motor function significantly improved starting from the second week. The infarction volume in the eMSC group was significantly smaller than that in the PBS control group at 4 weeks after infusion. The results of this study show that when administered intravenously, eMSCs differentiated into neuronal and endothelial cells, reduced the infarction volume, and improved behavioral functional outcome significantly in transient focal cerebral ischemia.
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PMID:Neuroprotective effects of mesenchymal stem cells derived from human embryonic stem cells in transient focal cerebral ischemia in rats. 1920 81

Recent studies have shown that similar to cerebral gray matter (mainly composed of neuronal perikarya), white matter (composed of axons and glias) is vulnerable to ischemia. Edaravone, a free radical scavenger, has neuroprotective effects against focal cerebral ischemia even in humans. In this study, we investigated the time course and the severity of both gray and white matter damage following global cerebral ischemia by cardiac arrest, and examined whether edaravone protected the gray and the white matter. Male Sprague-Dawley rats were used. Global cerebral ischemia was induced by 5 min of cardiac arrest and resuscitation (CAR). Edaravone, 3 mg/kg, was administered intravenously either immediately or 60 min after CAR. The morphological damage was assessed by cresyl violet staining. The microtubule-associated protein 2 (a maker of neuronal perikarya and dendrites), the beta amyloid precursor protein (the accumulation of which is a maker of axonal damage), and the ionized calcium binding adaptor molecule 1 (a marker of microglia) were stained for immunohistochemical analysis. Significant neuronal perikaryal damage and marked microglial activation were observed in the hippocampal CA1 region with little axonal damage one week after CAR. Two weeks after CAR, the perikaryal damage and microglial activation were unchanged, but obvious axonal damage occurred. Administration of edaravone 60 min after CAR significantly mitigated the perikaryal damage, the axonal damage, and the microglial activation. Our results show that axonal damage develops slower than perikaryal damage and that edaravone can protect both gray and white matter after CAR in rats.
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PMID:Edaravone, a free radical scavenger, mitigates both gray and white matter damages after global cerebral ischemia in rats. 1941 May 62

Decreased cerebral blood flow causes cognitive impairments and neuronal injury in the progressive age-related neurodegenerative disorders such as Alzheimer's disease (AD) and vascular dementia. In the present study, we for the first time found that nobiletin, a novel leading compound for AD therapy, improved cerebral ischemia-induced memory deficits in vivo. Treatment with 50 mg/kg of nobiletin (i.p.) for the consecutive 7 days before and after brain ischemia significantly inhibited delayed neuronal death in the hippocampal CA1 neurons in a 20-min bilateral common carotid arteries occlusion (BCCAO) ischemia. However, the contextual memory assessed by passive avoidance task was not improved. On the other hand, a 5-min BCCAO-induced contextual memory deficit was significantly improved by the nobiletin treatment. In the 5-min BCCAO mice, Western blot analysis evidently showed that the levels of synaptic proteins, including calcium/calmodulin-dependent protein kinase II (CaMKII), microtubule-associated protein 2 (MAP2) and glutamate receptor 1 (GluR1), significantly decreased in the hippocampal CA1 region. The nobiletin treatment prevented the reduction in CaMKII, MAP2 and GluR1 protein levels in the hippocampal CA1 region, accompanied by restoration of both ERK and CREB phosphorylation and CaMKII autophosphorylation. Consistent with the restored CaMKII and ERK phosphorylation, an electrophysiological study showed that the impaired hippocampal long-term potentiation (LTP) observed in the 5-min ischemic mice was significantly improved by the nobiletin treatment. These findings suggest that the activation of CaMKII and ERK signaling in part mediates improvement of ischemia-induced learning and memory deficits by nobiletin.
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PMID:Nobiletin improves brain ischemia-induced learning and memory deficits through stimulation of CaMKII and CREB phosphorylation. 1964 72

Using a fully implanted cortical electrical stimulation (CES) device with low-frequency burst impulse train, we investigated the effects of CES alone on behavioral recovery and surface density of dendritic structure in a rat model of middle cerebral artery occlusion (MCAO). After MCAO in rats, magnetic resonance imaging (MRI) was used to confirm cortex infarction and to identify a location for implantation of stimulating electrode over the peri-infarct cortex. The device was implanted on the 6th day after MCAO with CES then lasting for 16 days. The stimulation program consisted of two sessions lasting half an hour in the morning (0.65 mA, 0.13 microC/phase) and in the afternoon (0.5 mA, 0.1 microC/phase). The stimulator delivered biphasic charge balanced pulses (pulse width=200 micros) with various frequencies of 50 Hz, 20 Hz and 5 Hz in repeated 10-s blocks. Rats in the CES group (n=12) spend a much shorter time to regain preoperative levels of body weight (BW) than those in the no stimulation (NS) group (n=9). In behavioral tests, the rats in the CES group showed greater functional recovery compared to the NS group. Moreover, the functional improvement coincided with an increase in surface density of dendritic processes immunoreactive to microtubule-associated protein 2 (MAP2) in peri-infarct cortex. These results suggest the feasibility of the fully implanted CES device and the efficacy of the new stimulation protocol alone to improve functional outcome and cortical neuronal structural plasticity following focal cerebral ischemia in rats.
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PMID:Cortical electrical stimulation alone enhances functional recovery and dendritic structures after focal cerebral ischemia in rats. 1994 38


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