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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress links diverse neuropathological conditions that include stroke, Parkinson's disease, and Alzheimer's disease and has been modeled in vitro with various paradigms that lead to neuronal cell death following the increased accumulation of reactive oxygen species. For example, immortalized neurons and immature primary cortical neurons undergo cell death in response to depletion of the antioxidant glutathione, which can be elicited by administration of glutamate at high concentrations. We have demonstrated previously that this glutamate-induced oxidative toxicity requires activation of the mitogen-activated protein kinase member ERK1/2, but the mechanisms by which this activation takes place in oxidatively stressed neurons are still not fully known. In this study, we demonstrate that during oxidative stress, ERK-directed phosphatases of both the serine/threonine- and tyrosine-directed classes are selectively and reversibly inhibited via a mechanism that is dependent upon the oxidation of cysteine thiols. Furthermore, the impact of ERK-directed phosphatases on ERK1/2 activation and oxidative toxicity in neurons was tested in a neuronal cell line and in primary cortical cultures. Overexpression of the highly ERK-specific phosphatase MKP3 and its catalytic mutant, MKP3 C293S, were neuroprotective in transiently transfected HT22 cells and primary neurons. The neuroprotective effect of the MKP3 C293S mutant, which enhances ERK1/2 phosphorylation but blocks its nuclear translocation, demonstrates the necessity for active ERK1/2 nuclear localization for oxidative toxicity in neurons. Together, these data implicate the inhibition of endogenous ERK-directed phosphatases as a mechanism that leads to aberrant ERK1/2 activation and nuclear accumulation during oxidative toxicity in neurons.
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PMID:Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons. 1557 67

Because of its favorable action profile in humans, melatonin is a particularly interesting candidate as a neuroprotectant in acute ischemic stroke. Until now, the signaling mechanisms mediating melatonin's neuroprotective actions remained essentially uninvestigated. Herein, we examined the effects of melatonin, administered either orally for 9 wk as a stroke prophylactic (4 mg/kg/day) or intraperitoneally immediately after reperfusion onset (4 mg/kg), on the activation of signal transduction pathways in mice submitted to 90 min of intraluminal middle cerebral artery occlusion, followed by 24 hr of reperfusion. In these studies, melatonin significantly reduced ischemic infarct size by approximately 30-35%, as compared with animals receiving diluent (sham) treatment, independent of whether the indole was administered prior to or after ischemia. Under both conditions, animals receiving melatonin exhibited elevated phosphorylated Akt levels in their brains, as determined by Western blots. Additionally, phosphorylation levels of mitogen-activated protein kinase/extracellular-regulated kinase (ERK)-1/-2 and Jun kinase (JNK)-1/-2 were increased following prophylactic, but not acute, melatonin treatment. Our data suggest a role of phosphatidyl inositol-3 kinase/Akt signaling in acute melatonin-induced neuroprotection, while ERK-1/-2 and/or JNK-1/-2 rather appear to be involved in melatonin's long-term effects.
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PMID:Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice. 1561 39

The cellular isoform of prion protein, PrPc, may confer neuroprotection in the brain, according to recent studies. To elucidate the role of PrPc in stroke pathology, we subjected PrPc-knockout (Prnp(0/0)), wild-type and PrPc-transgenic (tga20) mice to 30 min of intraluminal middle cerebral artery occlusion, followed by 3, 24 or 72 h reperfusion, and examined how PrPc levels influence brain injury and cell signaling. In immunohistochemical experiments and Western blots, we show that PrPc expression is absent in the brains of Prnp(0/0) mice, detectable in wild-type controls and approximately 4.0-fold elevated in tga20 mice. We provide evidence that PrPc deficiency increases infarct size by approximately 200%, while transgenic PrPc restores tissue viability, albeit not above levels in wild-type animals. To elucidate the mechanisms underlying Prnp(0/0)-induced injury, we performed Western blots, which revealed increased activities of ERK-1/-2, STAT-1 and caspase-3 in ischemic brains of Prnp(0/0)mice. Our data suggest a role of cytosolic signaling pathways in Prnp(0/0)-induced cell death.
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PMID:Aggravation of ischemic brain injury by prion protein deficiency: role of ERK-1/-2 and STAT-1. 1589 68

Epidemiological studies have linked the consumption of phenolic acids with reduced risk of cardiovascular diseases. In the present study, we sought to investigate whether caffeic acid, a phenolic acid which is abundant in normal diet, can antagonize angiotensin II (Ang II)-induced vascular smooth muscle cell (VSMC) proliferation in stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats, and if so, to elucidate the underlying cell signaling mechanisms. We exposed VSMCs to Ang II and caffeic acid and found that caffeic acid significantly inhibited intracellular superoxide anion generation (decreased from 127 +/- 6.3% to 100.3 +/- 6.6% of the control cells) and the cell proliferation induced by Ang II. Furthermore, caffeic acid significantly abolished the tyrosine phosphorylation of JAK2 (decreased from 7.4 +/- 0.6-fold to 2.4 +/- 0.6-fold at 2 min) and STAT1 (decreased from 1.8 +/- 0.2-fold to 0.5 +/- 0.1-fold at 2 min) and the phosphorylation of ERK1/2 (decreased from 99.2 +/- 10.2-fold to 49.8 +/- 10.9-fold at 2 min) that were induced by Ang II. These effects of caffeic acid were consistent with the inhibition of the proliferation of VSMCs by DPI, an NADPH oxidase inhibitor, and by AG-490, a JAK2 inhibitor. In conclusion, our findings suggest that caffeic acid attenuates the proliferative reaction of VSMCs to Ang II stimulation in both SHRSP and WKY rats by inhibiting the generation of reactive oxygen species and then partially blocking the JAK/STAT signaling cascade and the Ras/Raf-1/ERK1/2 cascade.
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PMID:Caffeic acid inhibits vascular smooth muscle cell proliferation induced by angiotensin II in stroke-prone spontaneously hypertensive rats. 1613 68

The link between membrane phospholipids and different intracellular signal transduction pathways affected by cerebral ischaemia is unclear. CDP-choline, a major neuronal membrane lipid precursor and its intracellular target proteins and transcription factors were studied to further understand its role in ischaemic stroke. Cerebral ischaemia was produced by distal, permanent occlusion of the middle cerebral artery (MCAO) in the rat. Animals receiving 500 mg/kg of CDP-choline in 0.5 ml of 0.9% saline, intraperitoneally, 24 h and 1 h before MCAO and 23 h after MCAO demonstrated a notable reduction in the phosphorylation of MAP-kinase family members, ERK1/2 and MEK1/2, as well as Elk-1 transcription factor, compared with control animals treated with 0.5 ml of 0.9% saline. Immunohistochemistry showed a particular reduction in immunoreactivity in glia. The effects of CDP-choline on intracellular mechanisms of signal transduction, suggests that this molecule may play a key role in recovery after ischaemic stroke.
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PMID:Citicoline inhibits MAP kinase signalling pathways after focal cerebral ischaemia. 1625 56

This study was to examine the alterations in the phosphorylation of mitogen-activated protein kinase (MAPK) family in transient brain ischemia under a hyperglycemia and to highlight the molecular mechanisms by which hyperglycemia exacerbates brain damage resulting from stroke. Extracellular signal-regulated protein kinase (ERK) expression was studied in rats subjected to global brain ischemia with pre-ischemic normoglycemic (CIN) and hyperglycemic (CIH) conditions. In another group, the hyperglycemic ischemic rats were pretreated with ERK inhibitor U0126 (U0126). Increased phospho-ERK1/2 immunoreactive neurons in the cingulate cortex and hippocampal CA3 were detected in CIN after ischemia and reperfusion. The numbers of phospho-ERK1/2-positive neurons were further increased significantly in CIH compared to the CIN. Pretreatment with U0126 in CIH rats significantly decreased ERK1/2 immunoreactive cells. Western blot analyses confirmed that phospho-ERK1/2 increased significantly after 30 min ischemia and reperfusion compared to non-ischemic controls in both the CIN and CIH groups. The increase of phospho-ERK1/2 was more prominent in the CIH than in the CIN group after 3 and 6h of reperfusion. Treatment with U0126 significantly reduced phospho-ERK1/2 in the CIH group. The findings presented here suggest that ERK1/2 may play a role in mediating neuronal cells death under hyperglycemic condition.
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PMID:Hyperglycemia increased brain ischemia injury through extracellular signal-regulated protein Kinase. 1634 98

Cerebrovascular deposits of beta-amyloid (Abeta) peptides are found in Alzheimer's disease and cerebral amyloid angiopathy with stroke or dementia. Dysregulations of angiogenesis, the blood-brain barrier and other critical endothelial cell (EC) functions have been implicated in aggravating chronic hypoperfusion in AD brain. We have used cultured ECs to model the effects of beta-amyloid on the activated phosphorylation states of multifunctional serine/threonine kinases since these are differentially involved in the survival, proliferation and migration aspects of angiogenesis. Serum-starved EC cultures containing amyloid-beta peptides underwent a 2- to 3-fold increase in nuclear pyknosis. Under growth conditions with sublethal doses of beta-amyloid, loss of cell membrane integrity and inhibition of cell proliferation were observed. By contrast, cell migration was the most sensitive to Abeta since inhibition was significant already at 1 muM (P = 0.01, migration vs. proliferation). In previous work, intracellular Abeta accumulation was shown toxic to ECs and Akt function. Here, extracellular Abeta peptides do not alter Akt activation, resulting instead in proportionate decreases in the phosphorylations of the MAPKs: ERK1/2 and p38 (starting at 1 microM). This inhibitory action occurs proximal to MEK1/2 activation, possibly through interference with growth factor receptor coupling. Levels of phospho-JNK remained unchanged. Addition of PD98059, but not LY294002, resulted in a similar decrease in activated ERK1/2 levels and inhibition of EC migration. Transfection of ERK1/2 into Abeta-poisoned ECs functionally rescued migration. The marked effect of extracellular Abeta on the migration component of angiogenesis is associated with inhibition of MAPK signaling, while Akt-dependent cell survival appears more affected by cellular Abeta.
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PMID:Dissociation of ERK and Akt signaling in endothelial cell angiogenic responses to beta-amyloid. 1642 23

To investigate the association between hyperinsulinemia and cardiac hypertrophy, we treated rats with insulin for 7 wk and assessed effects on myocardial growth, vascularization, and fibrosis in relation to the expression of angiotensin II receptors (AT-R). We also characterized insulin signaling pathways believed to promote myocyte growth and interact with proliferative responses mediated by G protein-coupled receptors, and we assessed myocardial insulin receptor substrate-1 (IRS-1) and p110 alpha catalytic and p85 regulatory subunits of phospatidylinositol 3 kinase (PI3K), Akt, MEK, ERK1/2, and S6 kinase-1 (S6K1). Left ventricular (LV) geometry and performance were evaluated echocardiographically. Insulin decreased AT1a-R mRNA expression but increased protein levels and increased AT2-R mRNA and protein levels and phosphorylation of IRS-1 (Ser374/Tyr989), MEK1/2 (Ser218/Ser222), ERK1/2 (Thr202/Tyr204), S6K1 (Thr421/Ser424/Thr389), Akt (Thr308/Thr308), and PI3K p110 alpha but not of p85 (Tyr508). Insulin increased LV mass and relative wall thickness and reduced stroke volume and cardiac output. Histochemical examination demonstrated myocyte hypertrophy and increases in interstitial fibrosis. Metoprolol plus insulin prevented the increase in relative wall thickness, decreased fibrosis, increased LV mass, and improved function seen with insulin alone. Thus our data demonstrate that chronic hyperinsulinemia decreases AT1a-to-AT2 ratio and increases MEK-ERK1/2 and S6K1 pathway activity related to hypertrophy. These changes might be crucial for increased cardiovascular growth and fibrosis and signs of impaired LV function.
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PMID:Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways. 1656 9

Endothelin(B) (ET(B)) receptors are upregulated in experimental stroke or after 24 hrs of organ culture. This upregulation is manifested both as stronger contraction and as an increase in ET(B) receptor messenger RNA (mRNA) levels. The present study was designed to evaluate the importance of protein kinases (c-Jun N-terminal kinase [JNK], protein kinase C [PKC], and extracellular signal-regulated kinase [ERK1/2]) in ET(B) receptor upregulation after organ culture. Rat basilar and mesenteric arteries were incubated for 24 hrs in Dulbecco's modified Eagle's medium (DMEM) with or without the PKC inhibitor, RO-31-7549; the ERK1/2 inhibitor, SB386023; or the JNK inhibitor, SP600125, added 3, 6, or 12 hrs after initiation of incubation. Subsequently, vessel segments were mounted in myographs and the contractile responses to ET-1 and sarafotoxin 6c were studied. The ET(B) and ET(A) receptor mRNA levels were determined with a real-time polymerase chain reaction (PCR). The cellular localization and protein level of ET(B) receptors were evaluated by immunohistochemistry. The PKC and ERK1/2 inhibitors attenuated the contraction induced by S6c in the basilar arteries more than in the mesenteric arteries. The efficiency of the inhibitors was proportional to the incubation time. Real-time PCR showed a decrease in the ET(B) receptor mRNA levels in arteries treated with PKC or ERK inhibitors. The JNK inhibitor had a significant inhibitory effect on ET(B) receptor upregulation in the basilar arteries. Immunohistochemistry revealed that the ET(B) receptor upregulation occured in the smooth-muscle cells and that it had the same pattern as in the quantitative PCR. Our results show that the PKC, ERK1/2, and JNK are more important for the upregulation of contractile ET(B) receptors in cerebral arteries compared with mesenteric arteries. ERK1/2 seems to be more important for the ET(B) receptor upregulation, as compared with PKC and JNK. The evaluation of the time dependency suggests that the phenomenon can be reversed even after its initiation.
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PMID:Involvement of protein kinases on the upregulation of endothelin receptors in rat basilar and mesenteric arteries. 1656 36

Based on its trophic influence on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for stroke treatment. VEGF's survival-promoting effects are purchased at the expense of an increased blood brain barrier permeability, which potentially compromises tissue survival. The mechanisms via which VEGF protects the brain against ischemia remained unknown. We examined signaling pathways underlying VEGF's neuroprotective activity in our transgenic mouse line, which expresses human VEGF165 under a neuron-specific enolase (NSE) promoter. We show that VEGF receptor-2 (Flk-1) is expressed on ischemic neurons and astrocytes and is activated by VEGF. Following 90-min episodes of middle cerebral artery occlusion, VEGF increased phosphorylated (but not total) Akt and ERK-1/-2 and reduced phosphorylated mitogen activated protein kinase/p38 and c-Jun NH2-terminal kinase (JNK)-1/-2 levels, at the same time decreasing inducible NO synthase expression in ischemic neurons. Inhibition of Akt with Wortmannin reversed VEGF's neuroprotective properties, diminished brain swelling, and restored the vascular permeability induced by VEGF to below levels in WT animals. The aggravation of brain injury by Wortmannin was associated with the restitution of p38, but not of JNK-1/-2, ERK-1/-2, or inducible NOS (iNOS). Our data demonstrate that VEGF mediates both neuroprotection and blood brain barrier permeability via the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Based on our observation that VEGF neuroprotection and vascular leakage depend on PI3K/Akt, which is putatively regulated by VEGF receptor-2, we predict that it may not easily be possible to make use of VEGF's neuroprotective function without accepting its unfavorable consequence, the increased vascular permeability.
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PMID:The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF's neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia. 1664 Nov 98


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