Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stroke is a serious neurological disease and the third leading cause of death in the western world. In roughly 15 % of the cases, the cause is due to an intracranial haemorrhage, and the remaining 85 % represent ischemic strokes. Ischemic stroke is caused by the occlusion of a cerebral artery either by an embolus or by local thrombosis. Several studies have shown an involvement of the endothelin system in ischemic stroke. This review aims to examine the alterations of vascular endothelin receptor expression in ischemic stroke. Furthermore, studies of the intracellular signalling pathways leading to the enhanced expression of vascular endothelin receptors show that both protein kinase C (PKC) and mitogen activating protein kinase (MAPK) play important roles. The results from this work provide new perspectives on the pathophysiology of ischemic stroke, and give a possible explanation to the beneficial effects of treatment with PKC and MAPK inhibitors to limit the infarct volume.
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PMID:Cerebrovascular endothelin receptor upregulation in cerebral ischemia. 1914 37

The underlying pathogenesis of stroke is mediated by a variety of environmental risk factors as well as genetic ones. Thus, we have to evaluate the environmental factors precisely to identify the stroke-related gene polymorphisms. The Hisayama study, an epidemiological study of cardiovascular diseases, was established in 1961 in Hisayama, Japan. In 2002, a screening survey for the genetic study was performed in Hisayama. The Fukuoka Stroke Registry (FSR) is a hospital-based registration of stroke patients. Stroke specialists from eight medical centers in southern Japan have participated in FSR. In the present study, control and case subjects were recruited from the Hisayama study and FSR, respectively. We performed a genome-wide case-control study and found that a nonsynonymous SNP in PRKCH encoding a member of protein kinase C (PKCC eta) was significantly associated with brain infarction. As a candidate gene analysis, we investigated the role of NAD (P) H oxidase C242T polymorphism in the development of brain infarction. The C242T polymorphism was not associated with lacunar and atherothrombotic infarction; however, the presence of T-allele may have a protective role in the occurrence of atrial fibrillation and cardioembolic brain infarction. These studies may provide important information for the development of the therapeutic strategies against stroke.
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PMID:[Molecular epidemiology of cerebrovascular diseases; the Hisayama study and the Fukuoka Stroke Registry (FSR)]. 1919 8

Protein kinase C (PKC) activators possess potent neurotrophic and neuroprotective activity, thus indicating potential applications in treating neurodegenerative diseases, stroke and traumatic brain injury. Although some activators, such as bryostatin and gnidimacrin, have been tested as antitumor agents, others, such as phorbol esters, are potent tumor promoters. All PKC activators downregulate PKC at high concentrations and long application times. However, tumorigenic activators downregulate certain PKC isozymes, especially PKCdelta, more strongly. Tumorigenic activators possess unique structural features that could account for this difference. At concentrations that minimize PKC downregulation, PKC activators can improve long-term memory, reduce beta-amyloid levels, induce synaptogenesis, promote neuronal repair and inhibit cell proliferation. Intermittent, low concentrations of structurally specific, non-tumorigenic PKC activators, therefore, could offer therapeutic benefit for a variety of neurologic disorders.
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PMID:Neuroprotective versus tumorigenic protein kinase C activators. 1923 55

During the pre-hibernation season, arctic ground squirrels (AGS) can tolerate 8 min of asphyxial cardiac arrest (CA) without detectable brain pathology. Better understanding of the mechanisms regulating innate ischemia tolerance in AGS has the potential to facilitate the development of novel prophylactic agents to induce ischemic tolerance in patients at risk of stroke or CA. We hypothesized that neuroprotection in AGS involves robust maintenance of ion homeostasis similar to anoxia-tolerant turtles. Ion homeostasis was assessed by monitoring ischemic depolarization (ID) in cerebral cortex during CA in vivo and during oxygen glucose deprivation in vitro in acutely prepared hippocampal slices. In both models, the onset of ID was significantly delayed in AGS compared with rats. The epsilon protein kinase C (epsilonPKC) is a key mediator of neuroprotection and inhibits both Na+/K+-ATPase and voltage-gated sodium channels, primary mediators of the collapse of ion homeostasis during ischemia. The selective peptide inhibitor of epsilonPKC (epsilonV1-2) shortened the time to ID in brain slices from AGS but not in rats despite evidence that epsilonV1-2 decreased activation of epsilonPKC in brain slices from both rats and AGS. These results support the hypothesis that epsilonPKC activation delays the collapse of ion homeostasis during ischemia in AGS.
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PMID:Protein kinase C epsilon activation delays neuronal depolarization during cardiac arrest in the euthermic arctic ground squirrel. 1949 68

We recently showed that intraischemic moderate hypothermia (30 degrees C) reduces ischemic damage through the Akt pathway after permanent distal middle cerebral artery occlusion in rats. The only Akt pathway component preserved by hypothermia is phosphorylated phosphatase and tensin homolog deleted on chromosome 10 (p-PTEN), which suggests that p-PTEN may have a central role in neuroprotection. Reactive oxygen species (ROS) are critically involved in mediating ischemic damage after stroke by interacting with signaling molecules, including Akt, PTEN, and delta-protein kinase C (PKC). We investigated the protective mechanisms of moderate hypothermia on these signaling proteins after transient focal ischemia in rats. Early moderate hypothermia (3 h) was administered 15 mins before reperfusion, and delayed moderate hypothermia (3 h) was applied 15 mins after reperfusion. Our results indicate that early hypothermia reduced infarction, whereas delayed hypothermia did not. However, both early and delayed hypothermia maintained levels of Mn-SOD (superoxide dismutase) and phosphorylated Akt and blocked delta-PKC cleavage, suggesting that these factors may not be critical to the protection of hypothermia. Nevertheless, early hypothermia preserved p-PTEN levels after reperfusion, whereas delayed hypothermia did not. Furthermore, ROS inhibition maintained levels of p-PTEN after stroke. Together, these findings suggest that phosphorylation levels of PTEN are closely associated with the protective effect of early hypothermia against stroke.
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PMID:The protective effect of early hypothermia on PTEN phosphorylation correlates with free radical inhibition in rat stroke. 1955 7

Therapeutics for cerebral ischemia/hypoxia, which often results in ischemic stroke in humans, are a global unmet medical need. Here, we report that bryostatin-1, a highly potent protein kinase C (PKC) activator, interrupts pathophysiological molecular cascades and apoptosis triggered by cerebral ischemia/hypoxia, enhances neurotrophic activity, and induces synaptogenesis in rats. This postischemic therapeutic approach is further shown to preserve learning and memory capacity even 4 months later as well as long-term memory induced before the ischemic event. Our results of electromicroscopic and immunohistochemical analyses of neuronal and synaptic ultra-structure are consistent with a PKC-mediated synaptic remodeling and repair process that confers long-lasting preservation of spatial learning and memory before and after the cerebral ischemic/hypoxic event, suggesting a previously undescribed therapeutic modality for cerebral ischemia/hypoxia and ischemic stroke.
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PMID:Postischemic PKC activation rescues retrograde and anterograde long-term memory. 1966 90

Blood-brain barrier (BBB) dysfunction contributes to the pathophysiology of cerebrovascular diseases such as stroke. In the present study, we investigated the role of PKC isoforms in aglycemic hypoxia-induced hyperpermeability using an in vitro model of the BBB consisting of mouse bEnd.3 cells. PKCbetaII and PKCdelta isoforms were activated during aglycemic hypoxia. CGP53353, a specific PKCbetaII inhibitor, significantly attenuated aglycemic hypoxia-induced BBB hyperpermeability and disruption of occludin and zonula occludens-1 (ZO-1), indicating a deleterious role of PKCbetaII in the regulation of BBB permeability during aglycemic hypoxia. Conversely, rottlerin, a specific PKCdelta inhibitor, exacerbated BBB hyperpermeability and tight junction (TJ) disruption during aglycemic hypoxia, indicating a protective role of PKCdelta against aglycemic hypoxia-induced BBB hyperpermeability. Furthermore, disruption of TJ proteins during aglycemic hypoxia was attenuated by PKCbetaII DN and PKCdelta WT overexpression, and aggravated by PKCbetaII WT and PKCdelta DN overexpression. These results suggest that PKCbetaII and PKCdelta counter-regulate BBB permeability during aglycemic hypoxia.
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PMID:Role of PKCbetaII and PKCdelta in blood-brain barrier permeability during aglycemic hypoxia. 1990 May 7

The use of opioid analgesics has a long history in clinical settings, although the functions of opioid receptors, especially their role in the brain, are not well understood yet. Recent studies have generated abundant new data on opioid receptor-mediated functions and the underlying mechanisms. The most exciting finding in the past decade is probably the neuroprotection against hypoxic/ischemic stress mediated by delta-opioid receptors (DOR). An up-regulation of DOR expression and the release of endogenous opioids may increase neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers, depending on stress duration and severity, different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of ionic homeostasis, an increase in pro-survival signaling (e.g., PKC-ERK-Bcl 2) and the enhanced anti-oxidative capacity. Recent data on DOR-mediated neuroprotection provide us a new concept of neuroprotection against neurological disorders and have a potentially significant impact on the prevention and treatment of some serious neurological conditions, such as stroke.
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PMID:A novel insight into neuroprotection against hypoxic/ischemic stress. 2002 93

Evidence is accumulating indicating that some protein kinase C (PKC) isozymes play an essential role in various phases as well as types of learning and memory. Abnormal functions of PKC signal cascades in the brains have been found to represent one of the earliest changes in patients with Alzheimer's disease (AD) and other types of memory deficits, including those related to cerebral ischemic/stroke events. In preclinical studies, an inhibition or impairment of PKC activity leads to compromised learning and memory, whereas an appropriate activation of some PKC isozymes results in an enhancement of learning and memory and/or antidementic effects against memory disorders. PKC activators not only increase activity of PKC isozymes and thereby restore PKC signaling activity, including neurotrophic activity, synaptic/structural remodeling, and synaptogenesis in the hippocampus and related cortical areas, but also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation in the brain. These observations strongly suggest that PKC isoform pharmacology may represent an attractive area for the development of cognition-enhancing agents and therapeutics against memory loss in the future.
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PMID:Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics. 2038 81

Arterial thrombosis, a major cause of myocardial infarction and stroke, is initiated by activation of blood platelets by subendothelial collagen. The protein kinase C (PKC) family centrally regulates platelet activation, and it is becoming clear that the individual PKC isoforms play distinct roles, some of which oppose each other. Here, for the first time, we address all four of the major platelet-expressed PKC isoforms, determining their comparative roles in regulating platelet adhesion to collagen and their subsequent activation under physiological flow conditions. Using mouse gene knock-out and pharmacological approaches in human platelets, we show that collagen-dependent alpha-granule secretion and thrombus formation are mediated by the conventional PKC isoforms, PKCalpha and PKCbeta, whereas the novel isoform, PKC, negatively regulates these events. PKCdelta also negatively regulates thrombus formation but not alpha-granule secretion. In addition, we demonstrate for the first time that individual PKC isoforms differentially regulate platelet calcium signaling and exposure of phosphatidylserine under flow. Although platelet deficient in PKCalpha or PKCbeta showed reduced calcium signaling and phosphatidylserine exposure, these responses were enhanced in the absence of PKC. In summary therefore, this direct comparison between individual subtypes of PKC, by standardized methodology under flow conditions, reveals that the four major PKCs expressed in platelets play distinct non-redundant roles, where conventional PKCs promote and novel PKCs inhibit thrombus formation on collagen.
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PMID:Functional divergence of platelet protein kinase C (PKC) isoforms in thrombus formation on collagen. 2047 8


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