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)

Mild metabolic stress may increase resistance of neurons in the brain to subsequent, more severe insults, as demonstrated by the ability of ischemic pre-conditioning and dietary restriction to protect neurons in experimental models of stroke- and age-related neurodegenerative disorders. In the present study we employed iodoacetic acid (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, to test the hypothesis that inhibition of glycolysis can protect neurons. Pre-treatment of cultured hippocampal neurons with IAA can protect them against cell death induced by glutamate, iron and trophic factor withdrawal. Surprisingly, protection occurred with concentrations of IAA (2-200 nM) much lower than those required to inhibit glycolysis. Pre-treatment with IAA results in suppression of oxyradical production and stabilization of mitochondrial function in neurons after exposure to oxidative insults. Levels of the stress heat-shock proteins HSP70 and HSP90, and of the anti-apoptotic protein Bcl-2, were increased in neurons exposed to IAA. Our data demonstrate that IAA can stimulate cytoprotective mechanisms within neurons, and suggest the possible use of IAA and related compounds in the prevention and/or treatment of neurodegenerative conditions.
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PMID:Iodoacetate protects hippocampal neurons against excitotoxic and oxidative injury: involvement of heat-shock proteins and Bcl-2. 1167 64

Estradiol reduces brain injury from many diseases, including stroke and trauma. To investigate the molecular mechanisms of this protection, the effects of 17-beta-estradiol on heat shock protein (HSP) expression were studied in normal male and female rats and in male gerbils after global ischemia. 17-beta-estradiol was given intraperitoneally (46 or 460 ng/kg, or 4.6 microg/kg) and Western blots performed for HSPs. 17-beta-estradiol increased hemeoxygenase-1, HSP25/27, and HSP70 in the brain of male and female rats. Six hours after the administration of 17-beta-estradiol, hemeoxygenase-1 increased 3.9-fold (460 ng/kg) and 5.4-fold (4.6 microg/kg), HSP25/27 increased 2.1-fold (4.6 microg/kg), and Hsp70 increased 2.3-fold (460 ng/kg). Immunocytochemistry showed that hemeoxygenase-1, HSP25/27,and HSP70 induction was localized to cerebral arteries in male rats, possibly in vascular smooth muscle cells. 17-beta-estradiol was injected intraperitoneally 20 minutes before transient occlusion of both carotids in adult gerbils. Six hours after global cerebral ischemia, 17-beta-estradiol (460 ng/kg) increased levels of hemeoxygenase-1 protein 2.4-fold compared with ischemia alone, and HSP25/27 levels increased 1.8-fold compared with ischemia alone. Hemeoxygenase-1 was induced in striatal oligodendrocytes and hippocampal neurons, and HSP25/27 levels increased in striatal astrocytes and hippocampal neurons. Finally, Western blot analysis confirmed that estrogen induced heat shock factor-1, providing a possible mechanism by which estrogen induces HSPs in brain and other tissues. The induction of HSPs may be an important mechanism for estrogen protection against cerebral ischemia and other types of injury.
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PMID:17-beta-estradiol induces heat shock proteins in brain arteries and potentiates ischemic heat shock protein induction in glia and neurons. 1182 16

Genetic polymorphisms of heat shock protein 70-kD (HSP70) gene family have recently been hypothesized to be risk factors for cerebral ischemia. However, no prospective epidemiological data evaluating this gene family are available. The present investigation was conducted to examine the possible associations between the HSP70-1 nucleotide 190. HSP70-2 nucleotide 1267, and HSP70-hom nucleotide 2437 polymorphisms and the incidence of stroke in a large cohort of initially healthy men. 14916 apparently healthy men were followed over a 12-year period for incident stroke. Employing a nested case-control study design, 338 study participants who developed stroke (cases) and 338 age- and smoking-matched study participants who remained healthy during follow-up (controls) were evaluated. All observed genotype frequencies were in Hardy-Weinberg equilibrium. The allele and genotype distributions of the polymorphisms tested were similar among cases and controls, such that the relative risk of future stroke was 0.89 for HSP70-1 nucleotide 190 (95%CI = 0.70-1.12; p = 0.31), 1.13 for HSP70-2 nucleotide 1267 (95%CI = 0.90-1.42: p = 0.29); and 0.89 for HSP70-hom nucleotide 2437 (95%CI = 0.65-1.21; p = 0.45), assuming an additive model. No evidence of association was observed assuming dominant or recessive mode of inheritance. In this large, prospective study, genetic polymorphisms in the HSP70 genes were not associated with risks of future stroke. Screening for these polymorphisms is unlikely to be a useful tool for risk assessment.
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PMID:A prospective evaluation of the heat shock protein 70 gene polymorphisms and the risk of stroke. 1200 44

Many studies have shown that a brief period of ischemia can protect against a subsequent severe ischemic event and this has been termed ischemic preconditioning (IPC). Most studies have been focused on neuroprotection, with only a little attention on cerebrovascular effects. This study examines the effect of IPC, induced by 15 minutes of middle cerebral artery occlusion (MCAO) in the rat, on brain edema formation and cerebrovascular injury induced by a permanent MCAO induced three days later. Brain edema formation was significantly reduced in IPC treated rats compared to non-IPC treated rats. IPC-treated rats also had reduced blood-brain barrier disruption and reduced cerebrovascular expression of heat shock protein 70, a marker of cell stress. These results indicate that IPC reduces cerebrovascular injury from subsequent permanent focal cerebral ischemia. Understanding the mechanisms involved may provide new therapeutic strategies for stroke.
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PMID:Effect of ischemic preconditioning on edema formation and cerebrovascular injury following focal cerebral ischemia. 1216 21

Lithium has long been a primary drug used to treat bipolar mood disorder, even though the drug's therapeutic mechanisms remain obscure. Recent studies demonstrate that lithium has neuroprotective effects against glutamate-induced excitotoxicity in cultured neurons and in vivo. The present study was undertaken to examine whether postinsult treatment with lithium reduces brain damage induced by cerebral ischemia. We found that s.c. injection of lithium dose dependently (0.5-3 mEq/kg) reduced infarct volume in the rat model of middle cerebral artery occlusionreperfusion. Infarct volume was reduced at a therapeutic dose of 1 mEq/kg even when administered up to 3 h after the onset of ischemia. Neurological deficits induced by ischemia were also reduced by daily administration of lithium over 1 week. Moreover, lithium treatment decreased the number of neurons showing DNA damage in the ischemic brain. These neuroprotective effects were associated with an up-regulation of cytoprotective heat shock protein 70 (HSP70) in the ischemic brain hemisphere as determined by immunohistochemistry and Western blotting analysis. Lithium-induced HSP70 up-regulation in the ischemic hemisphere was preceded by an increase in the DNA binding activity of heat shock factor 1, which regulates the transcription of HSP70. Physical variables and cerebral blood flow were unchanged by lithium treatment. Our results suggest that postinsult lithium treatment reduces both ischemia-induced brain damage and associated neurological deficits. Moreover, the heat shock response is likely to be involved in lithium's neuroprotective actions. Additionally, our studies indicate that lithium may have clinical utility for the treatment of patients with acute stroke.
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PMID:Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model. 1273 32

Recent data show that geldanamycin can protect the brain against stroke in vivo, and this may be due to induction of heat shock proteins. Our previous results show that heat shock protein 70 expression by retroviral transfection protects astrocytes from necrotic injury by combined oxygen-glucose deprivation, an in vitro model of ischemia. This study tested the ability of geldanamycin to protect astrocytes from either necrotic or apoptotic injury induced by oxygen-glucose deprivation. Astrocytes were pre-treated with 0.1 microgram ml-1 geldanamycin in the medium 4, 8, or 16 h before as well as during oxygen-glucose deprivation. Increased protein levels of heat shock protein 70 were observed after 8 h pre-treatment with geldanamycin and increased further at 16 h pre-treatment, as detected by immunoblotting. Geldanamycin pre-treatment protected mature astrocytes from necrotic cell death and young astrocytes from apoptotic death. Geldanamycin protection of astrocytes against in vitro ischemia is likely due to upregulation of heat shock protein 70.
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PMID:Geldanamycin reduces necrotic and apoptotic injury due to oxygen-glucose deprivation in astrocytes. 1457 85

In brain, a brief ischemic episode induces protection against a subsequent severe ischemic insult. This phenomenon is known as preconditioning-induced neural ischemic tolerance. An understanding of the molecular mechanisms leading to preconditioning helps in identifying potential therapeutic targets for preventing the post-stroke brain damage. The present study conducted the genomic and proteomic analysis of adult rat brain as a function of time following preconditioning induced by a 10-min transient middle cerebral artery (MCA) occlusion. GeneChip analysis showed induction of 40 putative neuroprotective transcripts between 3 to 72 h after preconditioning. These included heat-shock proteins, heme oxygenases, metallothioneins, signal transduction mediators, transcription factors, ion channels and apoptosis/plasticity-related transcripts. Real-time PCR confirmed the GeneChip data for the transcripts up-regulated after preconditioning. Two-dimensional gel electrophoresis combined with MALDI-TOF analysis showed increased expression of HSP70, HSP27, HSP90, guanylyl cyclase, muskelin, platelet activating factor receptor and beta-actin at 24 h after preconditioning. HSP70 protein induction after preconditioning was localized in the cortical pyramidal neurons. The infarct volume induced by focal ischemia (1-h MCA occlusion) was significantly smaller (by 38 +/- 7%, p < 0.05) in rats subjected to preconditioning 3 days before the insult. Preconditioning also prevented several gene expression changes induced by focal ischemia.
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PMID:Putative endogenous mediators of preconditioning-induced ischemic tolerance in rat brain identified by genomic and proteomic analysis. 1503 Mar 91

Endogenous opioids have been implicated in the pathway of tolerance to stresses. Hibernating tissues tolerate stress. Serum from hibernating woodchucks (hibernation induction trigger [HIT]), from summer nonhibernating animals (summer woodchuck active plasma [SWAP], and potential "hibernation opioid mimics" (D-Ala(2) D Leu(5) Enkephalin [DADLE]), and Deltorphin D (Delt D) were used as ischemic preconditioning agents (IPC) in an in vivo surgically induced cardiac ischemia rat model. Comparison of the IPC treatment was monitored by the molecular intensity of stress transcripts for polyubiquitin and HSP70 in Northern blot analyses. Delt D and HIT significantly reduced total polyubiquitin transcript expression, 2.1-fold and 1.4-fold, respectively, in ischemic tissue, while SWAP and DADLE did not differ from saline controls. The Delt D effect was sensitive to glibenclamide (Glb), a K(ATP) (potassium adenosine triphosphate) channel blocker. No inducible HSP70 was detected. The demonstration of an opioid IPC modulation of the ubiquitin stress pathway found here may be relevant for development of drug intervention in heart attacks and stroke.
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PMID:Alternative strategy for stress tolerance: opioids. 1512 52

The mood stabilizing drug lithium has emerged as a robust neuroprotective agent in preventing apoptosis of neurons. Long-term treatment with lithium effectively protects primary cultures of rat brain neurons from glutamate-induced, NMDA receptor-mediated excitotoxicity. This neuroprotection is accompanied by an inhibition of NMDA-receptor-mediated calcium influx, upregulation of anti-apoptotic Bcl-2, downregulation of pro-apoptotic p53 and Bax, and activation of cell survival factors. Lithium treatment antagonizes glutamate-induced activation of c-Jun-N-terminal kinase (JNK), p38 kinase, and AP-1 binding, which has a major role in cytotoxicity, and suppresses glutamate-induced loss of phosphorylated cAMP responsive element binding protein (CREB). Lithium also induces the expression of brain-derived neurotrophic factor (BDNF) and subsequent activation TrkB, the receptor for BDNF, in cortical neurons. The activation of BDNF/TrkB signaling is essential for the neuroprotective effects of this drug. In addition, lithium stimulates the proliferation of neuroblasts in primary cultures of CNS neurons. Lithium also shows neuroprotective effects in rodent models of diseases. In a rat model of stroke, post-insult treatment with lithium or valproate, another mood stabilizer, at therapeutic doses markedly reduces brain infarction and neurological deficits. This neuroprotection is associated with suppression of caspase-3 activation and induction of chaperone proteins such as heat shock protein 70. In a rat model of Huntington's disease (HD) in which an excitotoxin is unilaterally infused into the striatum, both long- and short-term pretreatment with lithium reduces DNA damage, caspase-3 activation, and loss of striatal neurons. This neuroprotection is associated with upregulation of Bcl-2. Lithium also induces cell proliferation near the injury site with a concomitant loss of proliferating cells in the subventricular zone. Some of these proliferating cells display neuronal or astroglial phenotypes. These results corroborate our findings obtained in primary neuronal cultures. The neuroprotective and neurotrophic actions of lithium have profound clinical implications. In addition to its present use in bipolar patients, lithium could be used to treat acute brain injuries such as stroke and chronic progressive neurodegenerative diseases.
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PMID:Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? 1558 3

Aged individuals experience the highest rate of stroke and have less functional recovery, but do not have larger infarcts. We hypothesized that aged individuals experience greater sublethal damage in peri-infarct cortex. Focal cortical stroke was produced in aged and young adult animals. After 30 min, 1, 3 and 5 days brain sections and Western blot were used to analyze markers of apoptotic cell death, oxidative DNA and protein damage, heat shock protein (HSP) 70 induction, total neuronal number and infarct size. Focal stroke produces significantly more oxidative DNA and protein damage and fewer cells with HSP70 induction in peri-infarct cortex of aged animals. There is no difference in infarct size or the number of cells undergoing apoptosis between aged and young adults. Stroke in the aged brain is associated with a greater degree of DNA and protein damage and a reduced stress response in intact, surviving tissue that surrounds the infarct.
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PMID:Increased oxidative protein and DNA damage but decreased stress response in the aged brain following experimental stroke. 1575 69


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