Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In helical strips of dog cerebral arteries exposed to Ca2+-free medium under hypoxic conditions (95% N2 and 5% CO2), prostaglandin (PG) F2 alpha produced a slight tonic contraction. The addition of Ca2+ evoked a phasic contraction followed by relaxation and a sustained contraction, and reoxygenation elicited an additional tonic contraction of moderate magnitude. When the PGF2 alpha-induced contraction was stabilized in Ca2+-free medium, reoxygenation contracted the arteries only slightly. Treatment with the stable PGI2 analogues PGI2 methylester and TRK-100 attenuated the contractions caused by PGF2 alpha and Ca2+ and abolished almost completely the reoxygenation-induced contraction. Treatment with nitroglycerin inhibited the contractions caused by PGF2 alpha and Ca2+, but did not significantly alter the contraction induced by reoxygenation. The Ca2+ entry blockers diltiazem, flunarizine, and felodipine did not alter the PGF2 alpha-induced contractions, but attenuated the contractions caused by Ca2+ and reoxygenation. The vasodilator agents used appear to interfere differently with the release of Ca2+ from intracellularly stored sites and the transmembrane Ca2+ influx through receptor-operated channels under hypoxia and normoxia. The cerebroarterial contraction caused by reoxygenation may be associated mainly with increased Ca2+ influx from receptor activation and tissue oxygenation, which is markedly suppressed by PGI2 analogues and moderately attenuated by Ca2+ entry blockers but not significantly influenced by nitroglycerin.
J Cereb Blood Flow Metab 1988 Dec
PMID:Reoxygenation and calcium-induced cerebroarterial contractions as affected by vasodilator agents. 314 91

Transforming growth factor-alpha (TGF-alpha) is a ligand for the epidermal growth factor (EGF) receptor (EGFR), and is more abundant than EGF in the brain. The authors studied whether administration of exogenous TGF-alpha into the brain can protect neurons against ischemia in a model of permanent middle cerebral artery (MCA) occlusion in the rat, and whether any effect of TGF-alpha was mediated by EGFR by administering 4,5-dianilinophthalimide (DAPH), a protein-tyrosine kinase inhibitor with high selectivity for EGFR. Rats received either TGF-alpha (10 or 25 ng), DAPH (100 ng), DAPH plus TGF-alpha (25 ng), or vehicle in the ipsilateral first ventricle. Drugs were administered twice: 30 minutes before and 30 minutes after MCA occlusion, and infarct volume was evaluated 24 hours later. Transforming growth factor-alpha at the dose of 25 ng caused a statistically significant reduction of infarct volume (60%) in relation to ischemic rats administered vehicle. This reduction was no longer seen when TGF-alpha was administered in combination with DAPH. The present results show that TGF-alpha can protect neurons from ischemic damage, and that this effect is mediated by EGFR. It is suggested that activation of EGFR-mediated intracellular signalling pathways contributes to the survival of neural cells susceptible to ischemic injury.
J Cereb Blood Flow Metab 1999 Feb
PMID:Transforming growth factor-alpha acting at the epidermal growth factor receptor reduces infarct volume after permanent middle cerebral artery occlusion in rats. 1002 66

Neurogenesis occurs throughout life in the dentate gyrus of hippocampus and subventricular zone, but this phenomenon has rarely been observed in other brain regions of adult mammals. The aim of the current study was to investigate the cell proliferation process in the ischemically challenged region-at-risk after focal cerebral ischemia in the adult rat brain. A reversible photothrombotic ring stroke model was used, which features sustained hypoperfusion followed by late spontaneous reperfusion and a remarkable morphologic tissue recovery in the anatomically well defined somatosensory cortical region-at-risk. Twelve-week-old male Wistar rats received repeated intraperitoneal injections of the cell proliferation specific marker 5-bromodeoxyuridine (BrdU) after stroke induction. Immunocytochemistry of coronal brain sections revealed that the majority of BrdU-positive cells were of glial, macrophage, and endothelial origin, whereas 3% to 6% of the BrdU-positive cells were double-labeled by BrdU and the neuronspecific marker Map-2 at 7 and 100 days after stroke onset in the region-at-risk. They were distributed randomly in cortical layers II-VI. Three-dimensional confocal analyses of BrdU and the neuronal-specific marker Neu N by double immunofluorescence confirmed their colocalization within the same cells at 72 hours and 30 days after stroke induction. This study suggests that, as a potential pathway for brain repair, new neurons can be generated in the cerebral cortex of adult rats after sublethal focal cerebral ischemia.
J Cereb Blood Flow Metab 2000 Aug
PMID:Cortical neurogenesis in adult rats after reversible photothrombotic stroke. 1095 Mar 77

Dreher (dr(J)) is an autosomal recessive mutation in the newly identified LIM homeobox gene, Lmx1a. The homozygous mutant phenotype includes misplaced neurons (heterotopia) in the cerebral cortex, cerebellum and hippocampus, which mimic the mild end of the spectrum of neuronal migration disorders in humans. Heterotopic neurons are found mainly in the normally cell-sparse layer I within the cerebral hemispheres of dr(J) homozygotes. Neu-N immunostaining confirms the neuronal nature of these heterotopic cells, while bromodeoxyuridine-birthdating shows that the misplaced neurons are generated predominantly during the late stages of corticogenesis (E15-E17), suggesting an over-migration of neurons destined for layer II. Immunohistochemistry for laminin, and staining of reticulin fibres, reveals disruption of the glial limiting membrane specifically overlying the areas of heterotopic neurons. Factor VIII (von Willebrand factor) staining shows an abnormal vascular network in layer I, associated with the fragmented glial limiting membrane. Layer I astrocytes, recognized by immunostaining for glial fibrillary acidic protein, exhibit attachment of their end feet to the fragmented glial limiting membrane. We suggest that disruption of the glial limiting membrane is central to the pathogenesis of heterotopic neurons in dreher, perhaps via defective radial glial-guided neuronal migration.
Cereb Cortex 2001 Jun
PMID:Neuronal migration defects in the Dreher (Lmx1a) mutant mouse: role of disorders of the glial limiting membrane. 1137 11

Mitogen-activated protein kinases, which play a crucial role in signal transduction, are activated by phosphorylation in response to a variety of mitogenic signals. In the present study, the authors used Western blot analysis and immunohistochemistry to show that phosphorylated extracellular signal-regulated protein kinase (p-ERK) and c-Jun NH2-terminal kinase (p-JNK), but not p38 mitogen-activated protein kinase, significantly increased in both the neurons and astrocytes after traumatic brain injury in the rat hippocampus. Different immunoreactivities of p-ERK and p-JNK were observed in the pyramidal cell layers and dentate hilar cells immediately after traumatic brain injury. Immunoreactivity for p-JNK was uniformly induced but was only transiently induced throughout all pyramidal cell layers. However, strong immunoreactivity for p-ERK was observed in the dentate hilar cells and the damaged CA3 neurons, along with the appearance of pyknotic morphologic changes. In addition, immunoreactivity for p-ERK was seen in astrocytes surrounding dentate and CA3 pyramidal neurons 6 hours after traumatic brain injury. These findings suggest that ERK and JNK but not p38 cascades may be closely involved in signal transduction in the rat hippocampus after traumatic brain injury.
J Cereb Blood Flow Metab 2002 Mar
PMID:Differential activation of mitogen-activated protein kinase pathways after traumatic brain injury in the rat hippocampus. 1189 38

It has been proposed that mitogen-activated protein kinase (MAPK) pathways may play a role in the regulation of pro-inflammatory cytokines, such as interlukine-1, during cerebral ischemia. Our previous study showed that extracellular-signal-regulated kinases 1 and 2 (ERK 1/2) were activated during focal cerebral ischemia in mice [J. Cereb. Blood Flow Metab. 20 (2000) 1320]. However, the effect of ERK 1/2 activation in focal cerebral ischemia is still unclear. In this study we reported that in vivo phospho-ERK 1/2 expression increased following 30 min of middle cerebral artery occlusion (MCAO) in the mouse brain in both the ischemic core and perifocal regions. Western blot analysis and immunohistochemistry demonstrated that pro-treatment with 1,4-diamino-2,3-dicyano-1,4-bis butadiene (U0126) [J. Biol. Chem. 273 (1998) 18623] could significantly inhibit mouse brain phospho-MEK 1/2 and phospho-ERK 1/2 expression after 1-2 h of MCAO (p<0.05). Compared to the control group of mice, brain infarct volume was significantly decreased after 24 h of MCAO in the U0126-treated mice (27+/-6 vs. 46+/-9 mm(2), p<0.05). Inhibition of the MEK/ERK 1/2 pathway also prevented downstream kinase Elk-1 phosphorylation, and further reduced cytokine IL-1beta mRNA, but not TNFalpha, IL-1alpha, or chemokine MIP-1alpha mRNA expression. Our data demonstrates that in vivo the close linking of MEK 1/2, ERK 1/2, Elk-1, and IL-1 mRNA expression in the cerebral ischemia animals suggests that ERK 1/2 pathway activation is important in pro-inflammatory cytokine IL-1beta signaling, which induces an inflammatory response and exacerbates ischemic brain injury. Inhibiting the ERK 1/2 pathway may therefore provide a novel approach for the reduction of ischemia-induced IL-1beta overexpression.
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PMID:Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia. 1467 Jun 31

Traumatic brain injury (TBI) leads to mossy fiber reorganization, which is considered to be a causative factor in the development of temporal lobe epilepsy. However, the underlying mechanism is not fully understood. Emerging evidence suggests that TrkB-ERK1/2-CREB/Elk-1 pathways are highly related to synaptic plasticity. This study used the rat fluid-percussion injury model to investigate activation of TrkB-ERK1/2-CREB/Elk-1 signaling pathways after TBI. Rats were subjected to 2.0-atm parasagittal TBI followed by 30 minutes, 4 hours, 24 hours, and 72 hours of recovery. After TBI, striking activation of TrkB-ERK1/2-CREB/Elk-1 signaling pathways in mossy fiber organization were observed with confocal microscopy and Western blot analysis. ERK1/2 was highly phosphorylated predominantly in hippocampal mossy fibers, whereas TrkB was phosphorylated both in the mossy fibers and the dentate gyrus region at 30 minutes and 4 hours of recovery after TBI. CREB was also activated at 30 minutes, peaked at 24 hours of recovery, and returned to the control level at 72 hours of recovery in dentate gyrus granule cells. Elk-1 phosphorylation was seen in CA3 neurons at 4 hours after TBI. The results suggest that the signaling pathways of TrkB-ERK1/2-CREB/Elk-1 are highly activated in mossy fiber organization, which may contribute to mossy fiber reorganization seen after TBI.
J Cereb Blood Flow Metab 2004 Aug
PMID:Changes in trkB-ERK1/2-CREB/Elk-1 pathways in hippocampal mossy fiber organization after traumatic brain injury. 1536 24

The expression profile of the protease-activated receptor-2 (PAR-2) and effects of PAR-2 gene knockout (PAR-2 KO) on the infarct size were investigated after 60 minutes of transient middle cerebral artery occlusion (tMCAO) in mice in relation to phosphorylated extracellular signal-regulated kinase (p-ERK) and astrocyte activation. PAR-2 was normally distributed mainly in neurons of the central nervous system (CNS), and strongly upregulated at 8-24 hours after tMCAO. Deficiency of PAR-2 gene significantly increased the infarct volume and the number of TUNEL-positive cells at 24 hours of reperfusion. The strong neuronal expression of p-ERK was induced at 5 minutes as a peak after reperfusion in wild-type mice, but the signal change was significantly reduced in PAR-2 KO mice. Astroglial activation was also greatly inhibited at 24 hours after tMCAO in PAR-2 KO mice. These results show that the deficiency of PAR-2 gene increases the acute ischemic cerebral injury associating with suppression of neuronal ERK activation and reactive astroglial activation.
J Cereb Blood Flow Metab 2005 Mar
PMID:Deficiency of PAR-2 gene increases acute focal ischemic brain injury. 1564 43

Molecular mechanisms underlying the role of statins in the induction of brain plasticity and subsequent improvement of neurologic outcome after treatment of stroke have not been adequately investigated. Here, we use both in vivo and in vitro studies to investigate the potential roles of two prominent factors, vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), in mediating brain plasticity after treatment of stroke with atorvastatin. Treatment of stroke in adult mice with atorvastatin daily for 14 days, starting at 24 hours after MCAO, shows significant improvement in functional recovery compared with control animals. Atorvastatin increases VEGF, VEGFR2 and BDNF expression in the ischemic border. Numbers of migrating neurons, developmental neurons and synaptophysin-positive cells as well as indices of angiogenesis were significantly increased in the atorvastatin treatment group, compared with controls. In addition, atorvastatin significantly increased brain subventricular zone (SVZ) explant cell migration in vitro. Anti-BDNF antibody significantly inhibited atorvastatin-induced SVZ explant cell migration, indicating a prominent role for BDNF in progenitor cell migration. Mouse brain endothelial cell culture expression of BDNF and VEGFR2 was significantly increased in atorvastatin-treated cells compared with control cells. Inhibition of VEGFR2 significantly decreased expression of BDNF in brain endothelial cells. These data indicate that atorvastatin promotes angiogenesis, brain plasticity and enhances functional recovery after stroke. In addition, VEGF, VEGFR2 and BDNF likely contribute to these restorative processes.
J Cereb Blood Flow Metab 2005 Feb
PMID:Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. 1567 29

HIV-1 Tat protein plays an important role in inducing monocyte infiltration into the brain and may alter the structure and functions of the blood-brain barrier (BBB). The BBB serves as a frontline defense system, protecting the central nervous system from infected monocytes entering the brain. Therefore, the aim of the present study was to examine the mechanisms of Tat effect on the integrity of the BBB in the mouse brain. Tat was injected into the right hippocampi of C57BL/6 mice and expression of tight junction protein zonula occludens-1 (ZO-1) was determined in control and treated mice. Tat administration resulted in decreased mRNA levels of ZO-1 and marked disruption of ZO-1 continuity. These changes were associated with accumulation of inflammatory cells in brain tissue of Tat-treated mice. Further experiments indicated that Tat-mediated alterations of redox-related signaling may be responsible for decreased ZO-1 expression. Specifically, injections with Tat resulted in activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and pretreatment with U 0126, a specific inhibitor of ERK kinase, effectively ameliorated the Tat-induced diminished ZO-1 levels. In addition, administration of N-acetylcysteine (NAC), a precursor of glutathione and a potent antioxidant, attenuated both Tat-induced ERK 1/2 activation and alterations in ZO-1 expression. These results indicate that Tat-induced oxidative stress can play an important role in affecting the integrity of the BBB through the ERK 1/2 pathway.
J Cereb Blood Flow Metab 2005 Oct
PMID:HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK 1/2 activation. 1582 13


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