Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A direct involvement of the antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO1) in neuroprotection has not yet been shown. The aim of this study was to examine changes, localization and role of NQO1 after different neuronal injury paradigms. In primary cultures of rat cortex the activity of NQO1 was measured after treatment with ethylcholine aziridinium (AF64A; 40 micro m), inducing mainly apoptotic cell death, or oxygen-glucose deprivation (OGD; 120 min), which combines features of apoptotic and necrotic cell death. After treatment with AF64A a significant NQO1 activation started after 24 h. Sixty minutes after OGD a significant early induction of the enzyme was observed, followed by a second increase 24 h later. Enzyme activity was preferentially localized in glial cells in control and injured cultures, however, expression also occurred in injured neuronal cells. Inhibition of the NQO1 activity by dicoumarol, cibacron blue or chrysin (1-100 nM) protected the cells both after exposure to AF64A or OGD as assessed by the decreased release of lactate dehydrogenase. Comparable results were obtained in vivo using a mouse model of focal cerebral ischaemia. Dicoumarol treatment (30 nmol intracerebroventricular) reduced the infarct volume by 29% (p = 0.005) 48 h after the insult. After chemical induction of NQO1 activity by t-butylhydroquinone in vitro neuronal damage was exaggerated. Our data suggest that the activity of NQO1 is a deteriorating rather than a protective factor in neuronal cell death.
 ...
PMID:Role of NAD(P)H:quinone oxidoreductase in the progression of neuronal cell death in vitro and following cerebral ischaemia in vivo. 1260 27

Transforming growth factor-alpha (TGF-alpha), a ligand of the epidermal growth factor receptor, reduces the infarct size after focal cerebral ischemia in rat, but the molecular basis underlying the protection is unknown. Excitotoxicity and global inhibition of translation are acknowledged to contribute significantly to the ischemic damage. Here we studied whether TGF-alpha can rescue neurons from excitotoxicity in vitro and how it affects calcium homeostasis, protein synthesis, and the associated Akt and extracellular signal-regulated kinase 1/2 (Erk1/2) intracellular signaling pathways in mixed neuron-glia cortical cultures. We found that 100 ng/ml TGF-alpha attenuated neuronal cell death induced by a 30-min exposure to 35 microM N-methyl-D-aspartic acid (NMDA) (as it reduced lactate dehydrogenase release, propidium iodide staining, and caspase-3 activation) and decreased the elevation of intracellular Ca2+ elicited by NMDA. TGF-alpha induced a prompt and sustained phosphorylation of Erk1/2 and prevented the loss of Akt-P induced by NMDA 3 h after exposure. The protective effect of TGF-alpha was completely prevented by PD 98059, an inhibitor of the Erk1/2 pathway. Studies of incorporation of [3H]leucine into proteins showed that NMDA decreased the rate of protein synthesis, and TGF-alpha attenuated this effect. TGF-alpha stimulated the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) but did not affect eIF2 alpha, two proteins involved in translation regulation. PD 98059 abrogated the TGF-alpha effect on eIF4E. Our data demonstrate that TGF-alpha exerts a neuroprotective action against NMDA toxicity, in which Erk1/2 activation plays a key role, and suggest that the underlying mechanisms involve recovery of translation inhibition, mediated at least in part by eIF4E phosphorylation.
 ...
PMID:Transforming growth factor-alpha attenuates N-methyl-D-aspartic acid toxicity in cortical cultures by preventing protein synthesis inhibition through an Erk1/2-dependent mechanism. 1277 Nov 52

Previous work has shown that hydroxysafflor yellow A (HSYA), extracted from Carthamus tinctorius L. markedly extended the coagulation time in mice and exhibited a significant antithrombotic effect in rats. The present study was conducted to demonstrate further its neuroprotective effects on cerebral ischemic injury in both in vivo and in vitro studies. In vivo, male Wistar-Kyoto (WKY) rats with middle cerebral artery occlusion (MCAO) were evaluated for neurological deficit scores followed by the treatment with a single dose of HSYA. Furthermore, the infarction area of the brain was assessed in the brain slices. In vitro, the effect of HSYA was tested in cultured fetal cortical cells exposed to glutamate and sodium cyanide (NaCN) to identify its neuroprotection against neurons damage. The results in vivo showed that sublingular vein injection of HSYA at doses of 3.0 mg/kg and 6.0 mg/kg exerted significant neuroprotective effects on rats with focal cerebral ischemic injury by significantly decreasing neurological deficit scores and reducing the infarct area compared with the saline group, HSYA at a dose of 6.0 mg/kg showed a similar potency as nimodipine at a dose of 0.2 mg/kg. Sublingular vein injection of HSYA at the dose of 1.5 mg/kg showed a neuroprotective effect, however, with no significant difference when compared with the saline group. Results in vitro showed that HSYA significantly inhibited neuron damage induced by exposure to glutamate and sodium cyanide (NaCN) in cultured fetal cortical cells. Noticeably, the neuroprotective action of HSYA on glutamate-mediated neuron injury was much better than that of HSYA on NaCN-induced neuron damage. All these findings suggest that HSYA might act as a potential neuroprotective agent useful in the treatment in focal cerebral ischemia. Abbreviations. HSYA:hydroxysafflor yellow A TTC:2,3,5-triphenyltetrazolium chloride MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide DMEM:Dulbecco's modified Eagle medium FCS:Fetal calf serum MCAO:middle cerebral artery occlusion ECA:external carotid artery ICA:internal carotid artery LDH:lactate dehydrogenase NMDA: N-methyl- D-aspartate
 ...
PMID:Neuroprotective effects of hydroxysafflor yellow A: in vivo and in vitro studies. 1280 24

Apolipoprotein E (ApoE) deficiency has been shown to adversely affect outcome after transient cerebral ischemia and head trauma. Since oxidative stress contributes to these injuries, the ability of ApoE to reduce irreversible oxidative damage was studied in primary mixed neuronal-glial cell cultures. Cells (13-16 days in vitro) were exposed to 50 microM hydrogen peroxide (H2O2) for 30 min, and toxicity was determined by the release of lactate dehydrogenase (LDH) 24 h after exposure. The presence of recombinant human ApoE2 (100, 300, or 1000 nM) in the culture media partially protected against oxidative injury. This protection was not reversed by pre-treatment with receptor associated protein. The NMDA receptor antagonist, MK-801, also provided partial protection against H2O2 toxicity. The degree of protection was similar to that conferred by ApoE treatment. The protective effects of ApoE and MK-801 were not additive; no ApoE protection was observed in cultures treated with MK-801 prior to H2O2 exposure. ApoE treatment had no effect on H2O2 stimulated glutamate release, but did increase the rate of glutamate uptake via the high affinity glutamate transporter in H2O2 treated cultures. Pre-treatment with ApoE also conferred partial protection against glutamate-induced LDH release. Taken together, these findings suggest that ApoE protects mixed neuronal-glial cell cultures against irreversible oxidative injury from H2O2 by reducing secondary glutamate excitotoxicity.
 ...
PMID:Apolipoprotein E protects against oxidative stress in mixed neuronal-glial cell cultures by reducing glutamate toxicity. 1297 13

This in vitro study was designed to examine the efficacy of exogenous pyruvate and glucose as a fuel substrate to protect rat astrocytes from post-ischemic injury. Astrocytes were incubated in Kreb's buffer deprived of oxygen and glucose for 6 h (ischemia) followed by incubation with added pyruvate or glucose and normoxia for the next 6 h (reperfusion). The transformation of reactive astrocytes in response to various treatments was examined by immunostaining with glial fibrillary acidic protein. The extent of cell damage was evaluated in terms of lactate dehydrogenase leakage from the cells and altered intracellular redox status. The mechanism of cell death was determined by immunoblotting with cytochrome C, caspase-3 and PARP antibodies. The mechanism of the action of pyruvate was determined by measuring the activity of pyruvate dehydrogenase complex, and cellular metabolic status by measuring ATP levels. In comparison to glucose, supply of exogenous pyruvate restored the morphological integrity of post-ischemic astrocytes and prevented gliosis. Pyruvate prevented the cell death of post-ischemic astrocytes by inhibiting the leakage of lactate dehydrogenase, decreasing the redox ratio and restraining the activation of apoptotic events such as release of mitochondrial cytochrome c and fragmentation of caspase-3 and PARP. This study also suggests that pyruvate may accelerate its own metabolism by increasing the activity of pyruvate dehydrogenase and thus restores the cellular ATP levels in post-ischemic astrocytes. Use of pyruvate as an alternate fuel substrate may provide a possibility for the novel therapeutic approach to the treatment of cerebral ischemia.
 ...
PMID:Pyruvate ameliorates post ischemic injury of rat astrocytes and protects them against PARP mediated cell death. 1460 78

Ornithine decarboxylase (ODC) is considered the rate-limiting enzyme in polyamine biosynthesis, and an increase in putrescine after central nervous system (CNS) injury appears to be involved in neuronal death. Cerebral ischemia and reperfusion trigger an active series of metabolic events, which eventually lead to neuronal death. In the present study, ODC activity was evaluated following transient focal cerebral ischemia and reperfusion in rat. The middle cerebral artery (MCA) was occluded for 2 h in male rats with an intraluminal suture technique. Animals were sacrificed between 3 and 48 h of reperfusion following MCA occlusion, and ODC activity was assayed in cortex and striatum. ODC activity was also estimated in an in vitro ischemia model using primary rat cortical neuron cultures, at 6-24 h reoxygenation following 1 h oxygen-glucose deprivation (OGD). In cortex, following ischemia, ODC activity was increased at 3 h (P < .05), reached peak levels by 6-9 h (P < .001) and returned to sham levels by 48 h reperfusion. In striatum the ODC activity followed a similar time course, but returned to basal levels by 24 h. This suggests that ODC activity is upregulated in rat CNS following transient focal ischemia and its time course of activation is region specific. In vitro, ODC activity showed a significant rise only at 24 h reoxygenation following ischemic insult. The release of lactate dehydrogenase (LDH), an indicator for cell damage, was also significantly elevated after OGD. 0.25 mM alpha-difluoromethylornithine (DFMO) inhibited ischemia-induced ODC activity, whereas a 10-mM dose of DFMO appears to provide some neuroprotection by suppressing both ODC activity and LDH release in neuronal cultures, suggesting the involvement of polyamines in the development of neuronal cell death.
 ...
PMID:Ornithine decarboxylase activity in in vivo and in vitro models of cerebral ischemia. 1464 27

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, reduce the incidence of strokes and reduce infarct volume after cerebral ischemia in mice. Excitoxicity caused by overstimulation of glutamate receptors is a major cause of neuronal death after an ischemic brain insult. Experiments presented here explored whether statins protect cultured neurons from excitotoxic death caused by the glutamate receptor agonist NMDA. Treatment with statins preserved NMDA receptor-expressing cortical neurons and potently and substantially reduced lactate dehydrogenase release caused by exposure of embryonic mouse neocortical cultures to NMDA. The rank order of neuroprotective potency was rosuvastatin = simvastatin > atorvastatin = mevastatin > pravastatin, which is similar to the known rank order of potency for inhibition of the HMG-CoA reductase enzyme. Resistance of cultures to NMDA excitotoxicity developed after several days of statin exposure. Neuroprotection by rosuvastatin was coincident with a decrease in cell sterols and occurred with a similar potency as inhibition of cholesterol biosynthesis. Neuroprotection was substantially attenuated by cotreatment with either mevalonate or cholesterol and was mimicked by acute treatment with the cholesterol-extracting agent beta-cyclodextrin, suggesting that neuroprotection was mediated by depletion of a cellular pool of cholesterol because of the inhibition of cholesterol biosynthesis. These results suggest the possibility that, in addition to effects on cerebrovascular function, statins have the potential to render cortical neurons more resistant to NMDA-induced excitotoxic death as a result of changes in cell cholesterol homeostasis.
 ...
PMID:3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity. 1465 68

To obtain more information on the cerebral ischemia and reperfusion injury under desflurane anesthesia, we compared the infarct volume and lactate dehydrogenase (LDH) activity in rats subjected to focal cerebral ischemia during different concentration of desflurane anesthesia. Male Long-Evans rats weighing 270-350 g were anesthetized with desflurane in air at 1.0, 1.25 or 1.5 MAC whereas rats in the control group received intraperitoneal chloral hydrate (400 mg/kg) anesthesia. Cerebral infarction was induced by microsurgical procedures with ligation of the right middle cerebral artery (MCA) and clipping of the bilateral common carotid arteries (CCA) for 60 minutes. The rats were sacrificed 24 hours later, serial brain slices of 2mm thickness were taken and stained for the measurement of the infarct area. Cellular damage was evaluated by measuring the LDH level in the plasma. Desflurane (1.0, 1.25 or 1.5 MAC by inhalation) and chloral hydrate (400 mg/kg; ip.) did not produce any changes in pH, blood gases, heart rate or mean arterial blood pressure. In the rats subjected to focal cerebral ischemia, the volume of infarction was significantly less in the desflurane groups in all three different concentrations than in the chloral hydrate group. The changes of LDH activity in plasma also correlated with the result of the infarct volume. Our study suggests that desflurane may offer a neuroprotective effect such as decreased infarct volume after focal cerebral ischemia.
 ...
PMID:The effect of desflurane on ameliorating cerebral infarction in rats subjected to focal cerebral ischemia-reperfusion injury. 1501 Feb 64

Acid-sensing ion channel (ASIC) 1a subunit is expressed in synapses of central neurons where it contributes to synaptic plasticity. However, whether these channels can conduct Ca(2+) and thereby raise the cytosolic Ca(2+) concentration, [Ca(2+)](c), and possibly alter neuronal physiology has been uncertain. We found that extracellular acidosis opened ASIC1a channels, which provided a pathway for Ca(2+) entry and elevated [Ca(2+)](c) in wild-type, but not ASIC1(-/-), hippocampal neurons. Acid application also raised [Ca(2+)](c) and evoked Ca(2+) currents in heterologous cells expressing ASIC1a. Although ASIC2a is also expressed in central neurons, neither ASIC2a homomultimeric channels nor ASIC1a/2a heteromultimers showed H(+)-activated [Ca(2+)](c) elevation or Ca(2+) currents. Because extracellular acidosis accompanying cerebral ischemia contributes to neuronal injury, we tested the effect of acidosis on cell death measured as lactate dehydrogenase release. Eliminating ASIC1a from neurons or treating ASIC1a-expressing cells with the ASIC blocker amiloride attenuated acidosis-induced cell injury. These results indicate that ASIC1a provides a non-voltage-gated pathway for Ca(2+) to enter neurons. Thus, it may provide a target for modulation of [Ca(2+)](c).
 ...
PMID:Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. 1508 29

Nicotinamide (vitamin B(3)) reduces the infarct volume following focal cerebral ischemia in rats; however, its mechanism of action has not been reported. After cerebral ischemia and/or reperfusion, reactive oxygen species (ROS) and reactive nitrogen species may be generated by inflammatory cells through several cellular pathways, which can lead to intracellular calcium influx and cell damage. Therefore, we investigated the mechanisms of action of nicotinamide in neuroprotection under conditions of hypoxia/reoxygenation. Results showed that nicotinamide significantly protected rat primary cortical cells from hypoxia by reducing lactate dehydrogenase release with 1 h of oxygen-glucose deprivation (OGD) stress. ROS production and calcium influx in neuronal cells during OGD were dose-dependently diminished by up to 10 mM nicotinamide (p < 0.01). This effect was further examined with OGD/reoxygenation (H/R). Cells were stained with the fluorescent dye 4,6-diamidino-2-phenylindole (DAPI) or antibodies against anti-microtubule-associated protein-2 and cleaved caspase-3. Apoptotic cells were studied using Western blotting of cytochrome c and cleaved caspase-3. Results showed that vitamin B(3) reduced cell injury, caspase-3 cleavage and nuclear condensation (DAPI staining) in neuronal cells under H/R. In addition, nicotinamide diminished c-fos and zif268 immediate-early gene expressions following OGD. Taken together, these results indicate that the neuroprotective effect of nicotinamide might occur through these mechanisms in this in vitro ischemia/reperfusion model.
 ...
PMID:Protective effect of nicotinamide on neuronal cells under oxygen and glucose deprivation and hypoxia/reoxygenation. 1515 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>