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)

The present study focused on the mechanism of cytoprotective effect of aniracetam on the primary rat astrocyte cultures exposed to simulated ischemia conditions in vitro. To study these mechanisms, the aniracetam-mediated modulation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/Akt kinase pathways was determined. Simulated in vitro ischemia caused death of approximately 35% of astrocytes via apoptosis and decreased cell viability about 50% at 8 h. Exposure to aniracetam at concentrations of 0.1-10 microM in these conditions significantly decreased the number of apoptotic cells. Moreover, the intensification of 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolinum bromide (MTT) conversion and the decrease of lactate dehydrogenase (LDH) release after 1 and 10 microM aniracetam treatment were observed indicating a significant increase in cell viability. When cultured astrocytes were incubated during 8 h simulated ischemia with [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] (U0126), an extracellular regulated kinase 1 and 2 (Erk1/2) inhibitor or wortmannin, a phosphatidylinositol 3-kinase (PI3 kinase)/Akt inhibitor, the cell apoptosis was accelerated. These effects of used kinase inhibitors (both U0126 and wortmannin) were antagonized by adding 1 and 10 microM aniracetam to the culture medium. In addition, aniracetam significantly stimulated of phospho-Erk1/2 kinase and phospho-Akt expression. Maximum levels of Erk1/2 and Akt activation were observed as a result of treatment with 10 microM aniracetam. U0126 and wortmannin markedly attenuated the effects of aniracetam on expression of activated kinases. Results of the present study indicate that both Erk1/2 and PI 3-K/Akt kinase pathways are vital for cytoprotective effect of aniracetam.
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PMID:Erk1/2 and Akt kinases are involved in the protective effect of aniracetam in astrocytes subjected to simulated ischemia in vitro. 1521 64

Keishi-bukuryo-gan (Gui-Zhi-Fu-Ling-Wan) (KBG) is a traditional Chinese/Japanese medical (Kampo) formulation that has been administered to patients with "Oketsu" (blood stagnation) syndrome. In the process of neuronal cell death induced by brain ischemia, excessive generation of nitric oxide (NO) free radicals is implicated in the neurotoxicity. In the present study, we examined the protective effects of KBG and its constituent medicinal plants against NO donors, sodium nitroprusside (SNP) and 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (NOC18)-induced neuronal death in cultured rat cerebellar granule cells (CGCs). MTT assay showed cell viability to be significantly increased by the addition of KBG extract (KBGE) (100 microg/ml), Cinnamomi Cortex extract (CCE) (3, 10 and 30 microg/ml), Paeoniae Radix extract (PRE) (100 microg/ml) and Moutan Cortex extract (MCE) (10 and 30 microg/ml) compared with exposure to SNP (30 microM, 24 h) only. Also, cell viability was significantly increased by the addition of KBGE (100 and 300 microg/ml), CCE (30 and 100 microg/ml), PRE (100 and 300 microg/ml) and MCE (30 and 100 microg/ml) compared with exposure to NOC 18 (100 microM, 48 h) only. Persicae Semen extract and Hoelen extract did not protect against NO donor-induced neuronal death. These results suggest that KBG has protective effect against NO-mediated neuronal death in cultured CGCs and that it is derived from Cinnamomi Cortex, Paeoniae Radix and Moutan Cortex.
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PMID:Protective effect of keishi-bukuryo-gan and its constituent medicinal plants against nitric oxide donor-induced neuronal death in cultured cerebellar granule cells. 1533 Apr 95

Brain ischemia brings about hypoxic insults. Hypoxia is one of the major pathological factors inducing neuronal injury and central nervous system infection. We studied the involvement of mitogen-activated protein (MAP) kinase in hypoxia-induced apoptosis using cobalt chloride in C6 glioma cells. In vitro cytotoxicity of cobalt chloride was tested by MTT assay. Its IC(50) value was 400 microM. The DNA fragment became evident after incubation of the cells with 300 microM cobalt chloride for 24 h. We also evidenced nuclear cleavage with morphological changes of the cells undergoing apoptosis with electron microscopy. Next, we examined the signal pathway of cobalt chloride-induced apoptosis in C6 cells. The activation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) started to increase at 1 h and was activated further at 6 h after treatment of 400 M cobalt chloride. In addition, pretreatment of PD98059 inhibited cobalt chloride-induced apoptotic cell morphology in Electron Microscopy. These results suggest that cobalt chloride is able to induce the apoptotic activity in C6 glioma cells, and its apoptotic mechanism may be associated with signal transduction via MAP kinase (ERK 1/2).
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PMID:Cobalt chloride-induced apoptosis and extracellular signal-regulated protein kinase 1/2 activation in rat C6 glioma cells. 1546 37

Celsior solution (CS), a new preservation solution in thoracic organ transplantation, was evaluated for its efficacy in cold preservation of human liver endothelial cells (HLEC) and was compared to University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK, Custodiol). HLEC cultures were preserved at 4 degrees C in CS, UW, and HTK, for 2, 6, 12, 24, and 48 hours, with 6 hours of reperfusion. Levels of lactate dehydrogenase (LDH), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and adenosine 5'-triphosphate (ATP) were measured after each interval of ischemia and the respective phase of reperfusion. Preservation injury of HLEC as measured by LDH release, intracellular ATP level, and MTT reduction were overall significantly (P <or= .01, P <or= .01, P < .05, respectively) lower in UW than in CS and HTK. CS demonstrates a modest superiority to HTK in HLEC preservation. Furthermore, cold preservation remains the main cause of preservation injury of HLEC regardless of the preservation solution used. Additionally, the maintenance of a high intracellular ATP level of HLEC after ischemia and reperfusion, as shown by UW, could be taken as a beneficial effect, particularly in long-term ischemia. In conclusion, our cell culture model reveals the order of efficacy to protect HLEC against preservation injury as: UW >> CS > HTK.
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PMID:UW is superior to Celsior and HTK in the protection of human liver endothelial cells against preservation injury. 1555 36

Cardiac myocyte loss, regardless of insult, can trigger compensatory myocardial remodeling leading to heart failure. Identifying mediators of cardiac myocyte survival may advance clinical efforts toward myocardial preservation. Angiopoietin-1 limits ischemia-induced cardiac injury. This benefit is ascribed to angiogenesis because the receptor, tie2, is largely endothelial-specific. We propose that direct, non-tie2 interactions of angiopoietin-1 on cardiac myocytes contribute to this cardioprotection. We found that mouse C2C12 skeletal myocytes lack tie2, yet dose-dependently adhered to angiopoietin-1 and angiopoietin-2 similarly to laminin, fibronectin, vitronectin, and more than to collagen-I, -III, and -IV. Adhesion was divalent cation-mediated (Mn2+, Ca2+, not Mg2+), blocked with EDTA/EGTA, RGD-based peptides, and select integrin subunit antibodies. Similar findings were obtained with human skeletal myocytes (HSMs) and freshly isolated rat neonatal cardiac myocytes (NCMs). Furthermore, angiopoietin-1 conferred significant survival advantage exceeding that of most cell matrices, which was not fully explained by differences in cell adhesion. Angiopoietin-1 promoted survival of serum-starved C2C12, HSM, and NCM (MTT, trypan blue) and prevented taxol-induced apoptosis (caspase-3). Immobilized and soluble angiopoietin-1 phosphorylated Akt(S473) and MAPK(p42/44), (not FAK(Y397)) in C2C12 more than in endothelial cells and more than did angiopoietin-2 or cell matrices. EDTA, RGD-based peptides, and some integrin antibodies blocked these responses. Angiopoietin-1 activated HSM and NCM Akt(S473) and MAPK(p42/44) survival pathways. We propose that this novel function contributes to developmental and cardioprotective actions of angiopoietin-1 presently attributed to vascular effects alone. Angiopoietin-1 may prove therapeutically valuable in cardiac remodeling by supporting myocyte viability and preserving pump function. The full text of this article is available online at http://circres.ahajournals.org.
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PMID:Angiopoietin-1 promotes cardiac and skeletal myocyte survival through integrins. 1569 86

Cerebral ischemia-reperfusion leads to vascular dysfunction characterized by endothelial cell injury or death. In the present study, we used an in vitro model to elucidate mechanisms of human brain microvascular endothelial cell (HBMEC) injury after episodic ischemia-reperfusion. Near-confluent HBMEC cultures were exposed to intermittent hypoxia-reoxygenation (HX/RO) and, at different recovery time points, cell viability was assessed by the MTT assay, apoptotic death by fluorescence microscopy of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL)-positive cells, and nuclear translocation of apoptosis-inducing factor (AIF) and cleavage of poly(ADP-ribose) polymerase-1 (PARP-1) by immunoblotting of subcellular fractions. Reductions in HBMEC viability were proportional to the number of HX/RO cycles, and not the total duration of hypoxia. Using four cycles of 1-h HX with 1 h of intervening normoxic RO, cell viability was reduced 30% to 40% between 12 and 48 h. Treatment with the PARP-1 inhibitors 3-aminobenzamide or 4-amino-1,8-naphthalimide during the insult improved HBMEC viability at 24 h after insult, and resulted in dose-dependent reductions in TUNEL-positivity at 16 h after insult, but not if these treatments were delayed by 4 h. HX/RO-induced increases in nuclear AIF translocation, as well as PARP-1 cleavage, were also reduced dose-dependently at 4 h after insult by the inhibitors. The caspase inhibitor z-VAD-fmk blocked PARP-1 cleavage, but did not affect AIF translocation and was only modestly cytoprotective. These findings indicate that PARP-1 activation and a PARP-1-dependent, caspase-independent, nuclear translocation of AIF contribute to apoptotic cerebral endothelial cell death after ischemia-reperfusion, underscoring the potential for ischemic microvascular protection by inhibiting PARP activation or preventing AIF translocation.
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PMID:Cerebral endothelial cell apoptosis after ischemia-reperfusion: role of PARP activation and AIF translocation. 1572 91

To study the dynamic changes of CT perfusion parameters during the first 12 h in the embolic cerebral ischemia models. Local cerebral ischemia model were established in 7 New Zealand white rabbits. All CT scans were performed with a GE Lightspeed 16 multislice CT. Following the baseline scan, further CT perfusion scans were performed at the same locations 20 min, 1-6 h and 8, 10 and 12 h after the embolus delivery. Maps of all parameters were obtained by CT perfusion software at each time point. The brains, taken 12 h after the scan, were sliced corresponding to the positions of the CT slices and stained by 2,3,5-triphenyltetrazolium chloride (TTC). On the basis of the TTC results, the ischemic sides were divided into 3 regions: core, penumbra and the relatively normal region. The changes of all parameters were then divided into 3 stages. In the first two hours (the first stage), the CBV dropped more remarkably in the core than in the penumbra but rose slightly in the relatively normal region while the CBF decreased and MTT, TTP extended in all regions to varying degrees. In the 2nd-5th h (the second stage), all the parameters fluctuated slightly around a certain level. In the 5th-12th h (the third stage), the CBV and CBF dropped, and MTT and TTP were prolonged or shortened slightly in the core and penumbra though much notably in the former while the CBV, CBF rose and MTT, TTP were shortened remarkably in the relatively normal region. We experimentally demonstrated that the location and extent of cerebral ischemia could be accurately assessed by CT perfusion imaging. The pathophysiology of the ischemia could be reflected by the CT perfusion to varying degrees.
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PMID:Dynamic changes of the CT perfusion parameters in the embolic model of cerebral ischemia. 1579 58

Perfusion-weighted imaging (PWI) measures can predict tissue outcome in acute ischemic stroke. Accuracy might be improved if differential tissue susceptibility to ischemia is considered. We present a novel voxel-by-voxel analysis to characterize cerebral blood flow (CBF) separately in gray (GM) and white matter (WM). Ten patients were scanned with inversion-recovery spin-echo EPI (IRSEPI), diffusion-weighted imaging (DWI), PWI<6 h from onset and fluid attenuated inversion-recovery (FLAIR) at 30 days. Image processing included coregistration to PWI, automatic segmentation of IRSEPI into GM, WM and CSF and semiautomatic segmentation of DWI/FLAIR to derive the acute and 30-day lesions. Five tissue compartments were defined: (1) 'Core' (abnormal acutely and at 30 days), (2) 'Growth' (or 'infarcted penumbra', abnormal only at 30 days), (3) 'Reversed' (abnormal acutely but normal at 30 days), (4) 'MTT-Delayed ' (tissue with delayed mean transit time but not part of the acute or 30-day lesion), and (5) 'Normal' brain. Cerebral blood flow in GM and WM of each compartment was obtained from quantitative maps. Gray matter and WM mean CBF in the growth region differed by 5.5 mL/100 g min (P=0.015). Mean CBF also differed significantly within normal and MTT-Delayed compartments. The difference in the reversed region approached statistical significance. In core, GM and WM CBF did not differ. The results suggest separate ischemic thresholds for GM and WM in stroke penumbra.
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PMID:A novel method to derive separate gray and white matter cerebral blood flow measures from MR imaging of acute ischemic stroke patients. 1588 45

Calcitonin gene-related peptide (CGRP) plays an important role in the mediation of protective effects observed in situations such as ischemic preconditioning in rat hearts. In this study, we investigated in H9c2 rat cardiomyoblasts if the protective effect of CGRP could be linked to an inhibitory effect on the apoptotic pathway. We also determined the specificity of observed effects by treatment with adrenomedullin (ADM) in stress conditions generated by 100 microM hydrogen peroxide. Using MTT assays, we demonstrate that a pretreatment with CGRP decreases by half the loss of cell viability induced by H(2)O(2). CGRP inhibits phosphatidylserine externalization, caspase 3 activation and DNA fragmentation due to oxidative stress. Using RT-PCR, we observed an increase in Bcl-2 mRNA expression induced by CGRP treatment. Dot blotting experiments showed that, in stress conditions, Bcl-2 protein level decreases while Bax is increased. CGRP administration prior to stress prevents these effects. The three-receptor activity modifying protein (RAMP) isotypes were detected by RT-PCR in H9c2 cells and in left ventricle rat tissue, RAMP1 and RAMP3 being the most abundant in both cases. RAMP1 expression was upregulated by CGRP while RAMP3 mRNA level was decreased. Cell viability assessed by MTT indicates that, contrary to CGRP, pretreatment of stressed cells with ADM, a RAMP2 agonist, fails to protect them while treatment with CGRP(8-37) (a RAMP1 and 2 inhibitor) abolished CGRP protective effect. Taken together, these data suggest that CGRP has antiapoptotic properties through the RAMP1/CRLR complex. CGRP could be used to prevent apoptosis in an ischemia-reperfusion context.
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PMID:Antiapoptotic effect of calcitonin gene-related peptide on oxidative stress-induced injury in H9c2 cardiomyocytes via the RAMP1/CRLR complex. 1624 45

The role of glutathione during ischemia/reperfusion is still a controversial issue. Glutathione should exert beneficial effects in the situation of ischemia/reperfusion due to its antioxidative potency. However, increasing survival time after transient ischemia and hypoxia has been reported for glutathione depleted cells. This work was aimed to analyse whether glutathione metabolism essentially contributes to redox energy failure and subsequent cell damage during ischemia/reperfusion. For this purpose, primary astrocyte rich cell cultures were subjected to 1 h hypoxia followed by up to 4 h reoxygenation in combination with substrate deprivation and glutathione depletion. The ability of the cells to reduce MTT was used to quantify the redox power of the cells. Inhibition of glutathione synthesis by L-buthionine-(S,R)-sulfoximine (BSO) caused depletion of cellular glutathione within 24 h and increase in MTT reduction by about 10% under normoxic conditions. Reoxygenation following 1 h of hypoxia was associated with decrease in MTT reduction which was enhanced by substrate deprivation. Glutathione depletion reduced hypoxia-induced decrease in MTT reduction. Three hours of substrate deprivation prior hypoxia resulted in lower levels of MTT reduction during reoxygenaton. Our data suggest that in situations of oxidative stress such as ischemia/reperfusion, glutathione metabolism may causes decrease of the cellular redox energy below a threshold level required for basic cellular functions finally resulting in cell injury.
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PMID:Consumption of redox energy by glutathione metabolism contributes to hypoxia/ reoxygenation-induced injury in astrocytes. 1658 44


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