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

Gliosis is a hypertrophic and hyperplastic response to many types of central nervous system injury, including trauma, stroke, seizure, as well as neurodegenerative and demyelinating disorders. Reactive astrocytes, a major component of the glial scar, express molecules that can both inhibit and promote axonal regeneration. ATP, which is released upon traumatic injury, hypoxia, and cell death, contributes to the gliotic response by binding to specific cell surface astrocytic P2 nucleotide receptors and evoking characteristic features of gliosis such as increased expression of glial fibrillary acidic protein (GFAP), generation and elongation of astrocytic processes, and cellular proliferation. Here, we review recent studies that demonstrate that (1) metabotropic, P2Y, and ionotropic, P2X, receptors expressed in astrocytes are coupled to protein kinase signaling pathways that regulate cellular proliferation, differentiation, and survival such as ERK and protein kinase B/Akt and (2) these P2 receptor/protein kinase cascades are activated after trauma induced by mechanical strain. We suggest that P2 receptor/protein kinase signaling pathways might provide novel therapeutic targets to regulate the formation of reactive astrocytes and the production of molecules that affect axonal regeneration and neurodegeneration.
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PMID:Signaling from P2 nucleotide receptors to protein kinase cascades induced by CNS injury: implications for reactive gliosis and neurodegeneration. 1595 14

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 mechanisms involving neuronal death after ischemic/hypoxic insult are complex, involving both rapid (excitotoxic) and delayed (apoptotic-like) processes. Recent evidence suggests that cell cycle regulators such as cyclin-dependent kinases are abnormally activated in neuropathological conditions, including stroke. However, the function of this activation is unclear. Here, we provide evidence that inhibition of the cell cycle regulator, Cdk4, and its activator, cyclinD1, plays critical roles in the delayed death component of ischemic/hypoxic stress by regulating the tumor suppressor retinoblastoma protein. In contrast, the excitotoxic component of ischemia/hypoxia is predominately regulated by Cdk5 and its activator p35, components of a cyclin-dependent kinase complex associated with neuronal development. Hence, our data both characterize the functional significance of the cell cycle Cdk4 and neuronal Cdk5 signals as well as define the pathways and circumstances by which they act to control ischemic/hypoxic damage.
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PMID:Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo. 1616 66

Two primary drugs used to treat bipolar mood disorder are lithium and valproate. Emerging evidence supports the notion that both mood stabilizers have neuroprotective effects. In primary cultures of rat cerebellar granule cells and cortical neurons, lithium and valproate robustly and potently protect against glutamate-induced, N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. The neuroprotective mechanisms involve inactivation of NMDA receptors through inhibition of NR2B tyrosine phosphorylation, activation of cell survival factors such as the PI 3-kinase/Akt signaling pathway, and induction of neurotrophic/neuroprotective proteins, including brain-derived neurotrophic factor, heat-shock protein (HSP), and Bcl-2. Both drugs are also effective against other forms of insults such as ER stress in neurally related cell types. The molecular targets likely involve glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC) for lithium and valproate, respectively. In a rat cerebral artery occlusion model of stroke, postinsult treatment with lithium or valproate reduces ischemia-induced brain infarction, caspase-3 activation, and neurological deficits, and these neuroprotective effects are associated with HSP70 upregulation and, in the case of valproate, HDAC inhibition. In a rat excitotoxic model of Huntington's disease in which an excitotoxin is infused into the striatum to activate NMDA receptors, short-term lithium pretreatment is sufficient to protect against DNA damage, caspase activation, and apoptosis of striatal neurons, and this neuroprotection is concurrent with Bcl-2 induction. Moreover, lithium treatment increases cell proliferation near the site of striatal injury, and some newborn cells have phenotypes of neurons and astroglia. Thus, lithium and valproate are potential drugs for treating some forms of neurodegenerative diseases.
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PMID:The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. 1617 24

Transplantation of bone marrow stromal cells improves animal neurological functional recovery after stroke. Astrocytes are known to provide structural, trophic and metabolic support for neurons. Thus astrocytes are critical for neural survival during post-ischemia. However, information on the effects of bone marrow stromal cells on astrocytic survival post-ischemia is unavailable. We investigated the influence of rat bone marrow stromal cells on rat astrocytic apoptosis and survival post-ischemia employing an anaerobic chamber. Our data indicate that rat bone marrow stromal cells reduce cell death and apoptosis, and increase the DNA proliferation rate in astrocytes post-ischemia. Mitogen-activated protein kinase kinase/extracellular signal regulated kinase and phosphoinositide 3-kinase/threonine protein kinase pathways are involved in cell survival. Western blot showed that rat bone marrow stromal cells activate these two pathways in astrocytes post-ischemia, and upregulate total extracellular signal regulated kinase 1/2 and threonine protein kinase. Since astrocytes produce various neurotrophic factors, we performed reverse transcription polymerase chain reaction to investigate rat bone marrow stromal cells' effect on astrocyte growth factor gene expression post-ischemia. We observed that brain-derived neurotrophic factor, vascular endothelial growth factor and basic fibroblast growth factor gene expression was enhanced by rat bone marrow stromal cell coculture. These data suggest that bone marrow stromal cells increase astrocytic survival post-ischemic injury. This protective function might involve the activation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/threonine protein kinase pathways. Upregulation of brain-derived neurotrophic factor, vascular endothelial growth factor and basic fibroblast growth factor may also contribute to astrocyte survival.
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PMID:Bone marrow stromal cells increase astrocyte survival via upregulation of phosphoinositide 3-kinase/threonine protein kinase and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways and stimulate astrocyte trophic factor gene expression after anaerobic insult. 1619 97

Activation of the Akt/protein kinase B (PKB) kinase pathway can be neuroprotective after stroke. Akt is activated by growth factors via a phosphorylation-dependent pathway involving the kinases phosphoinositide 3 (PI3) kinase and phosphoinositide-dependent protein kinase-1 (PDK1) and is negatively regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Akt kinase blocks apoptosis by phosphorylating the substrates forkhead transcription factor (FKHR) and glycogen synthase kinase 3beta (GSK3beta). We found that intra-ischemic hypothermia (30 degrees C) reduced infarct size and improved functional outcomes up to 2 months. Changes in phosphorylation levels of Akt, as measured by Western blots and immunostaining, differed from levels of Akt activity measured in an in vitro assay in normothermic animals. Hypothermia blocked most of these changes and maintained Akt activity. Inhibition of PI3/Akt enlarged infarct size in hypothermic animals. Hypothermia improved phosphorylation of PDK1, PTEN, and FKHR. Hypothermia did not improve GSK3beta (Ser9) phosphorylation but blocked the nuclear translocation of phosphorylated beta-catenin (Ser33/37/Thr41) downstream of GSK3beta. Phosphorylation levels of PTEN, Akt, and Akt substrate decreased before apoptotic cytochrome c release and degradation of microtubule-associated protein-2, a marker of neuronal survival. Hypothermia may protect from ischemic damage in part by preserving Akt activity and attenuating the apoptotic effects of PTEN, PDK1, and FKHR.
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PMID:Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. 1623 83

Cell survival is regulated by the balance between death and survival signals. Previous studies have shown that the N-methyl-d-aspartate receptors (NMDARs) are responsible for the glutamate-induced excitotoxicity in the postischemic brain. Meanwhile, nerve growth factor (NGF) is critically involved in cell survival and neuroprotective effects via the extracellular signal-related kinase (ERK) pathway or the phosphatidylinositol 3-kinase (PI3-K) pathway mediated by the high affinity NGF receptor, tropomyosin-related kinase A (TrkA). Clinically, electroacupuncture (EA) has been shown to produce beneficial effects on stroke patients. However, the detailed mechanisms mediating the beneficial effects of EA on stroke are still unknown. In the present study, we found that EA treatment reversed the high expression of NR1 subunit and up-regulated the level of TrkA in a rat model of middle cerebral artery occlusion. Using protein kinase inhibitors of specific intracellular signaling pathways, we found that the neuroprotective effects of EA appear to be mediated by stimulation of the PI3-K pathway, but not ERK pathway. These findings may provide important experimental evidence for the clinical application of EA treatment for stroke patients.
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PMID:Electroacupuncture regulates NMDA receptor NR1 subunit expression via PI3-K pathway in a rat model of cerebral ischemia-reperfusion. 1628 3

MCT1 (monocarboxylic acid transporter 1) facilitates bidirectional monocarboxylic acid transport across membranes. MCT1 function and regulation have not been characterized previously in cerebral endothelial cells but may be important during normal cerebral energy metabolism and during brain diseases such as stroke. Here, by using the cytoplasmic pH indicator 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-acetoxymethyl ester, the initial rates of monocarboxylate-dependent cytoplasmic acidification were measured as an indication of MCT1 kinetic function in vitro using the rat brain endothelial cell (RBE4) model of blood-brain transport. The initial rate of L-lactate-dependent acidification was significantly inhibited by 5-10-min incubations with agonists of intracellular cAMP-dependent cell signaling pathways as follows: dibutyryl cAMP, forskolin, and isoproterenol. Isoproterenol reduced V(max) but did not affect K(m) values. The effects of forskolin were completely reversed by the protein kinase A inhibitor H89, whereas H89 alone increased transport rates. Cytoplasmic cAMP levels, measured by radioimmunoassay, were increased by forskolin or isoproterenol, and the effect of isoproterenol was inhibited by propranolol. MCT1-independent intracellular pH control mechanisms did not contribute to the forskolin or H89 effects on MCT1 kinetic function as determined with amiloride, monocarboxylate-independent acid loading, or the transport inhibitor alpha-cyano-4-hydroxycinnamate. The data demonstrate the direct modulation of MCT1 kinetic function in cerebral endothelial cells by agents known to affect the beta-adrenergic receptor/adenylyl cyclase/cAMP/protein kinase A intracellular signaling pathway.
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PMID:Modulation of monocarboxylic acid transporter-1 kinetic function by the cAMP signaling pathway in rat brain endothelial cells. 1630 11

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

Rho-associated kinases (ROCKs), the immediate downstream targets of RhoA, are ubiquitously expressed serine-threonine protein kinases that are involved in diverse cellular functions, including smooth muscle contraction, actin cytoskeleton organization, cell adhesion and motility, and gene expression. Recent studies have shown that ROCKs may play a pivotal role in cardiovascular diseases such as vasospastic angina, ischemic stroke, and heart failure. Indeed, inhibition of ROCKs by statins or other selective inhibitors leads to the upregulation and activation of endothelial nitric oxide synthase (eNOS) and reduction of vascular inflammation and atherosclerosis. Thus inhibition of ROCKs may contribute to some of the cholesterol-independent beneficial effects of statin therapy. Currently, two ROCK isoforms have been identified, ROCK1 and ROCK2. Because ROCK inhibitors are nonselective with respect to ROCK1 and ROCK2 and also, in some cases, may be nonspecific with respect to other ROCK-related kinases such as myristolated alanine-rich C kinase substrate (MARCKS), protein kinase A, and protein kinase C, the precise role of ROCKs in cardiovascular disease remains unknown. However, with the recent development of ROCK1- and ROCK2-knockout mice, further dissection of ROCK signaling pathways is now possible. Herein we review what is known about the physiological role of ROCKs in the cardiovascular system and speculate about how inhibition of ROCKs could provide cardiovascular benefits.
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PMID:Physiological role of ROCKs in the cardiovascular system. 1646 61


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