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

Perturbation of normal survival mechanisms may play a role in a large number of disease processes. Glutamate neurotoxicity, particularly when mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, has been hypothesized to underlie several types of acute brain injury, including stroke. Several neurological insults linked to excessive release of glutamate and neuronal death result in tyrosine kinase activation, including p44/42 mitogen activated protein (MAP) kinase. To further explore a role for MAP kinase activation in excitotoxicity, we used a novel tissue culture model to induce neurotoxicity. Removal of the endogenous blockade by Mg2+ of the NMDA receptor in cultured hippocampal neurons triggers a self perpetuating cycle of excitotoxicity, which has relatively slow onset, and is critically dependent on NMDA receptors and activation of voltage gated Na+ channels. These injury conditions led to a rapid phosphorylation of p44/42 that was blocked by MAP kinase kinase (MEK) inhibitors. MEK inhibition was associated with protection against synaptically mediated excitotoxicity. Interestingly, hippocampal neurons preconditioned by a sublethal exposure to Mg(2+)-free conditions were rendered resistant to injury induced by a subsequently longer exposure to this insult; the preconditioning effect was MAP kinase dependent. The MAP kinase signaling pathway can also promote polypeptide growth factor mediated neuronal survival. MAP kinase regulated pathways may act to promote survival or death, depending upon the cellular context in which they are activated.
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PMID:Neuronal protein kinase signaling cascades and excitotoxic cell death. 1146 62

Experimentally and clinically, stroke is followed by both acute and prolonged inflammatory responses characterized by the production of inflammatory cytokines and leukocyte infiltration into the brain. A debate on whether inflammation after stroke is neurotoxic or participates in brain repair remains unresolved. However, the need to pharmacologically control inflammatory amplification has been commonly acknowledged. The principal challenge of devising successful anti-inflammatory strategies for stroke is to understand molecular and temporal interplay of inflammatory and cell-death-inducing processes triggered by cerebral ischemia in both parenchymal and vascular brain cells. This article will review a number of experimental and clinically tested approaches to reduce brain inflammation and damage after stroke (e.g., anti-neutrophil, anti-ICAM-1, anti-cytokine strategies) and will suggest potential pathways where novel therapeutic targets may emerge, including transcriptional regulators of inflammatory gene expression (e.g., NF-kappaB, proteasome) and signaling pathways (e.g., ICE-cascade, MAPK/MKK/ERK cascade) linked to both inflammation and neuronal cell death. Finally, we will discuss applications of functional genomics technologies in the discovery of stroke diagnostics and therapies.
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PMID:Current and future therapeutic strategies to target inflammation in stroke. 1456 Nov 97

In response to cerebral ischemia, neurons activate survival/repair pathways in addition to death cascades. Activation of cyclic AMP-response-element-binding protein (CREB) is linked to neuroprotection in experimental animal models of stroke. However, a role of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MAPK/ERK or MEK), an upstream kinase for CREB, and its relation to CREB phosphorylation in neuroprotection in cerebral ischemia has not been delineated. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) significantly protected CA1 neurons after transient forebrain ischemia [J Neurosci 19 (1999b) 87.8]. The current study is to investigate whether NAMDA-induced neuroprotection occurs via the activation of ERK and its downstream effector, CREB. NAMDA induced ERK1/2 and CREB phosphorylation with increased survival of HC2S2 hippocampal neurons subjected to oxygen-glucose deprivation. These effects were reversed by U0126, a MEK kinase inhibitor. Similarly, animals treated with NAMDA following ischemia showed increased ERK and CREB phosphorylation in the CA1 subregion of the hippocampus during early reperfusion period with increased number of surviving neurons examined 7 days following ischemia. The NAMDA-induced neuroprotection was abolished by U0126 administered shortly after reperfusion. The results showed that the ERK-CREB signaling pathway might be involved in NAMDA-induced neuroprotection following transient global ischemia and imply that the activation of the pathway in neurons may be an effective therapeutic strategy to treat stroke or other neurological syndromes.
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PMID:A neuroprotective role of extracellular signal-regulated kinase in N-acetyl-O-methyldopamine-treated hippocampal neurons after exposure to in vitro and in vivo ischemia. 1466 49

Vascular endothelial growth factor (VEGF, occurring in several isoforms: VEGF-A, -B, -C, -D) is a well-known endothelial cell mitogen and vascular growth and permeability factor. Recent work done over the last few years has elucidated the important role of VEGF, which participates in the regulation of normal (physiological or therapeutic) and pathological angiogenesis (VEGF-A, VEGF-B) and lymphangiogenesis (VEGF-C, VEGF-D). VEGF has also been implicated in practically every stage of angiogenesis, yet its role in the initiation of new blood vessel creation appears to be the most important. In addition to its role as a key angiogenic factor, VEGF also possesses neurotrophic and neuroprotective activity both in the peripheral and in the central nervous system, exerting a direct action on neurons, Schwann cells, astrocytes, neural stem cells, and microglia. VEGF interacts with three subtypes of VEGF receptors occurring on the cellular membrane known as VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR), and VEGFR-3 (Flt-4). All these receptor types possess an internal tyrosin kinase domain. Interaction of VEGF with particular subtypes of receptors activates a circuit of signaling pathways, e.g. PI3K/Akt, Ras/Raf-MEK/Erk, eNOS/NO, and IP3/Ca2+. These participate in the generation of specific biological responses connected with proliferation, migration, increasing vascular permeability, or promoting endothelial cell survival. Recent findings from experiments performed on animals with experimentally evoked focal cerebral ischemia suggest that the neuroprotective activity of VEGF runs in parallel with its ability to promote neurogenesis and angiogenesis and that these effects may operate independently through multiple mechanisms. The above-mentioned three major features characterizing the neurobiological activity of VEGF, i.e. neuroprotection, neurogenesis, and angiogenesis, together with their possible functional link(s), provide the rationale for considering VEGF-based therapy as a promising future avenue for a more effective treatment of at least some neurodegenerative disorders and stroke. Moreover, the possibility of using neutralizing factors of VEGF or VEGF receptor antagonists may reveal a way of preventing many dangerous pathologies, including post-ischemic disturbances in cardiac and neurological disorders, tumor growth, or hypervascularization in avascular structures of the eye.
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PMID:[VEGF as an angiogenic, neurotrophic, and neuroprotective factor]. 1640 96

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

Although recent clinical trials have shown that amlodipine exerts antiatherogenic effects, the mechanism of these effects remains unknown. This study was designed to examine which signal transduction pathway might be important for the antiatherogenic property of amlodipine, as assessed by aortic smooth muscle cell (SMC) phenotypes in hypertension in vivo. Stroke-prone spontaneously hypertensive rats (SHRSP) were randomly treated with a vehicle, amlodipine, or enalapril while Wistar-Kyoto rats (WKY) used as controls were treated with only the vehicle. Both drugs were equally effective at reducing systolic blood pressure, and inhibiting the progression of aortic remodeling and fibrosis in comparison to those of vehicle-treated SHRSP. In the aortas of vehicle-treated SHRSP, the level of contractile-type smooth muscle (SM) myosin heavy chain (MHC) SM2 was significantly lower, whereas the level of synthetic-type MHC NMHC-B/SMemb was significantly higher compared with those in the WKY aortas. Compared to the vehicle-treated SHRSP group, both drugs significantly and equally shifted the aortic SMC phenotype in SHRSP toward the differentiated state by reducing NMHC-B/SMemb and increasing SM2. The levels of MKK6, p38 MAPK, MEK1 and p-42/44 ERK were significantly higher in the vehicle-treated SHRSP than in the WKY. Both drugs significantly reduced these values in the SHRSP aorta. Furthermore, the levels of MEK1 and p-42/44 ERK were significantly lower in the amlodipine- than in the enalapril-treated SHRSP group, whereas enalapril was more effective than amlodipine at increasing p-Akt and endothelial NO synthase in SHRSP aortas, which were significantly lower in the vehicle SHRSP group than in the WKY group. Thus, the MEK-ERK pathway might be one of the crucial determinants of the aortic SMC phenotype activated by amlodipine treatment of hypertension in vivo.
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PMID:Different effects of amlodipine and enalapril on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase pathway for induction of vascular smooth muscle cell differentiation in vivo. 1675 53

The protective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) in stroke models is poorly understood. We studied patterns of PACAP, vasoactive intestinal peptide, and the PACAP-selective receptor PAC1 after middle cerebral artery occlusion and neuroprotection by PACAP in cortical cultures exposed to oxygen/glucose deprivation (OGD). Within hours, focal ischemia caused a massive, NMDA receptor (NMDAR)-dependent up-regulation of PACAP in cortical pyramidal cells. PACAP expression dropped below the control level after 2 days and was normalized after 4 days. Vasoactive intestinal peptide expression was regulated oppositely to that of PACAP. PAC1 mRNA showed ubiquitous expression in neurons and astrocytes with minor changes after ischemia. In cultured cortical neurons PACAP27 strongly activated Erk1/2 at low and p38 MAP kinase at higher nanomolar concentrations via PAC1. In astrocyte cultures, effects of PACAP27 on Erk1/2 and p38 were weak. During OGD, neurons showed severely reduced Erk1/2 activity and dephosphorylation of Erk1/2-regulated Ser112 of pro-apoptotic Bad. PACAP27 stimulation counteracted Erk1/2 inactivation and Bad dephosphorylation during short-term OGD but was ineffective after expanded OGD. Consistently, PACAP27 caused MEK-dependent neuroprotection during mild but not severe hypoxic/ischemic stress. While PACAP27 protected neurons at 1-5 nmol/L, full PAC1 activation by 100 nmol/L PACAP exaggerated hypoxic/ischemic damage. PACAP27 stimulation of astrocytes increased the production of Akt-activating factors and conferred ischemic tolerance to neurons. Thus, ischemia-induced PACAP may act via neuronal and astroglial PAC1. PACAP confers protection to ischemic neurons by maintaining Erk1/2 signaling via neuronal PAC1 and by increasing neuroprotective factor production via astroglial PAC1.
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PMID:Pituitary adenylate cyclase-activating polypeptide is up-regulated in cortical pyramidal cells after focal ischemia and protects neurons from mild hypoxic/ischemic damage. 1786 5

Extracellular signal-regulated kinase 1/2 (ERK1/2), one of the best-characterized members of the mitogen-activated protein kinase (MAPK) family, mediates a range of activity from metabolism, motility, and inflammation to cell death and survival. It is phosphorylated and activated through a three-tiered MEK mode via cell surface receptors stimulated by growth factors or cytokines. The phosphorylated ERK1/2 level is usually increased after cerebral ischemia/reperfusion, but whether an increase in ERK1/2 phosphorylation is protective or detrimental is highly debatable. Much of the support for ERK1/2's role as a neuroprotectant against stroke stems from its apparent involvement in the beneficial effects of growth factors, estrogen, preconditioning, and hypothermia on the ischemic brain. Conversely, evidence supporting the detrimental effects of ERK1/2 activity is derived from its activation promoting inflammation and oxidative stress and its inhibition reducing ischemic damage. The dual potential of ERK1/2 actions in the ischemic brain is likely related to its responses to a diverse array of agonists and cell surface receptors. Plausibly, the ERK1/2 activity generated by cytokines and free radicals or other inflammatory factors after stroke may worsen ischemic damage, whereas the ERK1/2 activity produced by exogenous growth factors, estrogen, and preconditioning favors neuroprotection. Future experiments should be conducted to optimize the protective effect of ERK1/2 while blocking its detrimental actions.
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PMID:Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke. 1818 18

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease and conditions such as ischemic stroke affect millions of individuals annually and exert an enormous financial burden on society. A hallmark of these conditions is the abnormal loss of neurons. Currently, there are no effective strategies to prevent neuronal death in these pathologies. We report that several 2-arylidine and 2-hetarylidin derivatives of the 1,4-benzoxazines class of compounds are highly protective in tissue culture models of neurodegeneration. Results obtained using pharmcalogical inhibitors indicate that neuroprotection by these compounds does not involve the Raf-MEK-ERK or PI-3 kinase-Akt signaling pathways nor other survival-promoting molecules such as protein kinase A (PKA), calcium calmodulin kinase A (CaMK), and histone deacetylases (HDACs). We tested one of these compounds, (Z)-6-amino-2-(3',5'-dibromo-4'-hydroxybenzylidene)-2H-benzo[b][1,4]oxazin-3(4H)-one, designated as HSB-13, in the 3-nitropropionic acid (3-NP)-induced mouse model of Huntington's disease. HSB-13 reduced striatal degeneration and improved behavioral performance in mice administered with 3-NP. Furthermore, HSB-13 was protective in a Drosophila model of amyloid precursor protein (APP) toxicity. To understand how HSB-13 and other 1,4-benzoxazines protect neurons, we performed kinase profiling analyses. These analyses showed that HSB-13 inhibits GSK3, p38 MAPK, and cyclin-dependent kinases (CDKs). In comparison, another compound, called ASK-2a, that protects cerebellar granule neurons against low-potassium-induced death inhibits GSK3 and p38 MAPK but not CDKs. Despite its structural similarity to HSB-13, however, ASK-2a is incapable of protecting cortical neurons and HT22 cells against homocysteic acid (HCA)-induced or Abeta toxicity, suggesting that protection against HCA and Abeta depends on CDK inhibition. Compounds described in this study represent a novel therapeutic tool in the treatment of neurodegenerative diseases.
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PMID:Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration. 2014 21

Reactive astrocytes are traditionally thought to impede brain plasticity after stroke. However, we previously showed that reactive astrocytes may also contribute to stroke recovery, partly via the release of a nuclear protein called high-mobility group box 1 (HMGB1). Here, we investigate the mechanisms that allow stimulated astrocytes to release HMGB1. Exposure of rat primary astrocytes to IL-1beta for 24 h elicited a dose-dependent HMGB1 response. Immunostaining and western blots of cell lysates showed increased intracellular levels of HMGB1. Western blots confirmed that IL-1beta induced a release of HMGB1 into astrocyte conditioned media. MAP kinase signaling was involved. Levels of phospho-ERK were increased by IL-1beta, and the MEK/ERK inhibitor U0126 decreased HMGB1 upregulation in the stimulated astrocytes. Since HMGB1 is a nuclear protein, the role of the nuclear protein exporter, chromosome region maintenance 1 (CRM1), was assessed as a candidate mechanism for linking MAP kinase signaling to HMGB1 release. IL-1beta increased CRM1 expression in concert with a translocation of HMGB1 from nucleus into cytoplasm. Blockade of IL-1beta-stimulated HMGB1 release with the ERK inhibitor U0126 was accompanied by a downregulation of CRM1. Our findings reveal that IL-1beta stimulates the release of HMGB1 from activated astrocytes via ERK MAP kinase and CRM1 signaling. These data suggest a novel pathway by which inflammatory cytokines may enhance the ability of reactive astrocytes to release prorecovery mediators after stroke.
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PMID:Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes. 2022 44


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