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)

This study investigated the effects of the selective peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist WY14643 on ischemia/reperfusion (I/R) injury in the rat hippocampus. Transient cerebral ischemia (30 min), followed by 1-24 h reperfusion, significantly increased the generation of reactive oxygen species, nitric oxide (NO), and lipid peroxidation end-products, as well as markedly reducing levels of the endogenous antioxidant glutathione. Reperfusion for 3-6 h led to increased expression of the proteins heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1). Pretreatment with WY14643 suppressed oxidative stress and expression of HO-1, iNOS, and ICAM-1, but had no effect on COX-2. These effects are due to suppression of the activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB. The PPAR-alpha antagonist MK886 abolished the beneficial effects of WY14643. The levels of S100B protein, a marker of cerebral injury used in stroke trials to monitor injury, were high in the hippocampus of rats exposed to I/R, but markedly reduced by WY14643. We propose that WY14643 protects the brain against excessive oxidative stress and inflammation and may thus be useful in treating stroke.
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PMID:Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: effects of the PPAR-alpha agonist WY14643. 1686 91

Stroke is a devastating disease with limited treatment options. Recently, we found that the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists troglitazone and pioglitazone reduce injury and inflammation in a rat model of transient cerebral ischemia. The mechanism of this protection is unclear, as these agents can act through PPAR-gamma activation or through PPAR-gamma-independent mechanisms. Therefore, we examined PPAR-gamma expression, DNA binding and transcriptional activity following stroke. In addition, we used a PPAR-gamma antagonist, T0070907, to determine the role of PPAR-gamma during ischemia. Using immunohistochemical techniques and real-time PCR, we found low levels of PPAR-gamma mRNA and PPAR-gamma immunoreactivity in nonischemic brain; however, PPAR-gamma expression dramatically increased in ischemic neurons, peaking 24 h following middle cerebral artery occlusion. Interestingly, we found that in both vehicle- and agonist-treated brains, DNA binding was reduced in the ischemic hemisphere relative to the contralateral hemisphere. Expression of a PPAR-gamma target gene, lipoprotein lipase, was also reduced in ischemic relative to nonischemic brain. Both DNA binding and lipoprotein lipase expression were increased by the addition of the PPAR-gamma agonist rosiglitazone. Finally, we found that rosiglitazone-mediated protection after stroke was reversed by the PPAR-gamma antagonist T0070907. Interestingly, infarction size was also increased by T0070907 in the absence of PPAR-gamma agonist, suggesting that endogenous PPAR-gamma ligands may mitigate the effects of cerebral ischemia.
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PMID:Altered PPARgamma expression and activation after transient focal ischemia in rats. 1700 29

1. Stroke is accompanied by a robust inflammatory response, glutamate-mediated excitotoxicity, release of reactive oxygen species and apoptosis. Thiazolidinediones, which target the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-g, have been reported recently to exhibit potent anti-inflammatory and anti-oxidant actions and inhibit both neural excitotoxicity and apoptosis. 2. The present study was conducted to determine whether rosiglitazone, a potent thiazolidinedione for PPAR-g, would show efficacy against the cerebral infarction and neurological dysfunctions induced by embolic middle cerebral artery (MCA) occlusion in the rat. 3. Focal ischaemic injury was induced by embolizing a preformed clot into the MCA. Rosiglitazone was dissolved in dimethyl sulphoxide and injected i.p. 1 h before MCA occlusion at doses of 0.33, 0.1, 0.3 or 1 mg/kg. In addition, 1 mg/kg rosiglitazone was used immediately or 4 h after embolization. Forty-eight hours after MCA occlusion, brains were removed, sectioned and stained with a 2% solution of 2,3,5-triphenyltetrazolum chloride and analysed using a commercial image-processing software program. 4. When rosiglitazone was administered 1 h before embolization, it significantly reduced infarct volume by 48.2, 68.4% and 70.3% at doses of 0.1, 0.3 and 1 mg/kg, respectively (P < 0.001). Administration of rosiglitazone (1 mg/kg) immediately or 4 h after stroke also reduced infarct volume by 67 and 50.8%, respectively (P < 0.001). Rosiglitazone-treated rats also demonstrated improved neurological functions. However, there were no statistically significant differences between control and treated groups in terms of brain oedema at 48 h after ischaemic injury. 5. The findings of the present study may support the idea of a potential benefit of thiazolidinediones in the management of ischaemic stroke.
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PMID:Rosiglitazone, a peroxisome proliferator-activated receptor-gamma ligand, reduces infarction volume and neurological deficits in an embolic model of stroke. 1704 14

The peroxisome proliferator-activated receptor (PPAR) family of genes plays a major role in metabolic regulation. Unfortunately, the results of two recent, large event trials of PPAR agonists have been mixed. High rates of crossover to statin use confound the interpretation of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, which found a less than expected reduction in coronary and stroke events with fenofibrate. Of concern, nonsignificant increases in coronary and sudden deaths, thrombotic events, and pancreatitis occurred in the fenofibrate group. The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) also found a reduction in coronary and stroke events with pioglitazone compared with placebo in a population with diabetes and cardiovascular disease, but this benefit was counterbalanced by an increase in congestive heart failure as well as symptomatic edema. Further research is needed to determine the role of PPAR agonists in the prevention of cardiovascular disease.
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PMID:Update on PPAR agonists: the clinical significance of FIELD and PROACTIVE. 1716 49

1. Recently, we reported that 4-hydroxyderricin, one of the major chalcones in Angelica keiskei extract (ethyl acetate extract from the yellow liquid of stems), exerted hypotensive and lipid regulatory actions in stroke-prone spontaneously hypertensive rats (SHRSP). In the present study, we isolated xanthoangelol, another major chalcone in A. keiskei extract, and examined the effect of dietary xanthoangelol on blood pressure and lipid metabolism in SHRSP. 2. Six-week-old male SHRSP were fed diets containing 0.02% or 0.1% xanthoangelol (0.02 and 0.10 Xan, respectively) for 7 weeks, with free access to the diet and water. There were no significant changes in daily food intake, bodyweight or systolic blood pressure throughout the experimental period. Serum total cholesterol levels tended to decrease in the two experimental groups (albeit not significantly), which was due to a dose-dependent decrease in the cholesterol content of the low-density lipoprotein (LDL) fraction. These results suggest that dietary xanthoangelol decreases serum LDL levels. 3. In the liver, significant dose-dependent decreases in relative liver liver weight and total triglyceride content were seen in the 0.02 and 0.10 Xan groups. In addition, a significant decrease in total cholesterol content was found in the 0.10 Xan group, which may be due to an elevation of faecal cholesterol excretion in addition to the decrease in liver weight. 4. Investigation of the hepatic mRNA expression of proteins involved in lipid metabolism indicated that there was a significant increase in peroxisome proliferator-activated receptor (PPAR) alpha mRNA expression associated with the tendency for increases in acyl-coenzyme A (CoA) synthetase and acyl-CoA oxidase mRNA expression in the 0.10 Xan group, which may be responsible, at least in part, for the decrease in hepatic triglyceride content in the xanthoangelol-treated rats. In addition, a significant increase in LDL receptor mRNA expression in the 0.10 Xan group may be responsible, at least in part, for the decrease in serum LDL levels in the xanthoangelol-treated rats. 5. In conclusion, dietary xanthoangelol results in a reduction of serum LDL levels and decreases in total cholesterol and triglyceride contents in the liver of SHRSP. These beneficial effects are more effective following consumption of diet containing 0.10% xanthoangelol.
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PMID:Beneficial effect of xanthoangelol, a chalcone compound from Angelica keiskei, on lipid metabolism in stroke-prone spontaneously hypertensive rats. 1725 Jun 45

Thiazolidinediones (TZDs) are synthetic agonists of the ligand-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma). TZDs are known to curtail inflammation associated with peripheral organ ischemia. As inflammation precipitates the neuronal death after stroke, we tested the efficacy of TZDs in preventing brain damage following transient middle cerebral artery occlusion (MCAO) in adult rodents. As hypertension and diabetes complicate the stroke outcome, we also evaluated the efficacy of TZDs in hypertensive rats and type-2 diabetic mice subjected to transient MCAO. Pre-treatment as well as post-treatment with TZDs rosiglitazone and pioglitazone significantly decreased the infarct volume and neurological deficits in normotensive, normoglycemic, hypertensive and hyperglycemic rodents. Rosiglitazone neuroprotection was not enhanced by retinoic acid x receptor agonist 9-cis-retinoic acid, but was prevented by PPARgamma antagonist GW9662. Rosiglitazone significantly decreased the post-ischemic intercellular adhesion molecule-1 expression and extravasation of macrophages and neutrophils into brain. Rosiglitazone treatment curtailed the post-ischemic expression of the pro-inflammatory genes interleukin-1beta, interleukin-6, macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, cyclooxygenase-2, inducible nitric oxide synthase, early growth response-1, CCAAT/enhancer binding protein-beta and nuclear factor-kappa B, and increased the expression of the anti-oxidant enzymes catalase and copper/zinc-superoxide dismutase. Rosiglitazone also increased the expression of the anti-inflammatory gene suppressor of cytokine signaling-3 and prevented the phosphorylation of the transcription factor signal transducer and activator of transcription-3 after focal ischemia. Thus, PPARgamma activation with TZDs might be a potent therapeutic option for preventing inflammation and neuronal damage after stroke with promise in diabetic and hypertensive subjects.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. 1739 60

Ischemic stroke is burdened with a high morbidity and mortality in our society. However, there are few effective and largely available therapies for this devastating disease. In additon to advancing acute reperfusion therapies, there is a need to develop treatments aimed to promote repair and regeneration of brain tissue damaged by ischemia (neurorecovery). Therapeutic angiogenesis and vasculogenesis represent novel approaches of regenerative medicine that may help in the cure of patients with acute ischemic stroke. Translation of our knowledge about these processes from the bench to bedside is still underway. Although angiogenesis (the sprouting of new blood vessels from pre-existing vascular structures) is likely to contribute to neurorepair, the finality of the angiogenic response in acute ischemic stroke has not been fully elucidated. The first therapeutic approach to angiogenesis after ischemic stroke would be the modulation of the endogenous angiogenic response. In this setting, early instauration of physical activity, statins, and peroxisome proliferator-activated receptor-gamma agonists may enhance angiogenesis and neuroregeneration. Gene therapy with vascular growth factors has been successfully tested in patients affected by chronic myocardial and peripheral ischemia. Regarding brain ischemia, experiments in animal models have shown that the effect of these growth factors is critically affected by the dosage, route of delivery, and time of administration in relation to stroke onset. In addition, the optimal angiogenic substance is unknown. Finally, vectors for gene transfer should be further optimized. Therapeutic vasculogenesis consists of the administration of exogenous endothelial progenitor cells in order to enhance brain repair processes. Endothelial progenitor cells may be recruited in response to cerebral ischemia and participate in reparative vasculogenesis after acute ischemic stroke. Further research is needed to clarify their role and therapeutic applicability in human brain ischemia.
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PMID:The role of angiogenesis in damage and recovery from ischemic stroke. 1760 84

In the recent years, the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR-gamma agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Delta(12,14) prostaglandin J(2)), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory drugs) have shown anti-inflammatory and protective effects in several experimental models of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR-gamma agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes), as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR-gamma agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation.
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PMID:Regulation of Glial Cell Functions by PPAR-gamma Natural and Synthetic Agonists. 1846 25

Recent studies have demonstrated that peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists can protect the brain against excessive oxidative stress and inflammation in traumatic brain injury (TBI) and stroke through endogenous PPAR-alpha. However, it has not been investigated whether, and to what degree, cerebral expression of PPAR-alpha changes after TBI, especially in the human brain. In this study, 12 contused brain samples were obtained from 11 patients undergoing surgery for TBI 6 - 98 h after trauma. PPAR-alpha binding activity was measured by electrophoretic mobility shift assay, and temporal and cellular expression of PPAR-alpha by immunohistochemistry. The results showed that a persistent upregulation of PPAR-alpha binding activity and protein expression occurred in injured cortex after TBI, which peaked 24 - 72 h post-injury. Expression of PPAR-alpha was mainly located in glial and vascular endothelial cells with a little expression in the neurons. It is concluded that TBI could greatly upregulate the binding activity and protein expression of PPAR-alpha in injured human brain, which might be important in brain pathophysiology after TBI.
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PMID:Cortical expression of peroxisome proliferator-activated receptor-alpha after human brain contusion. 1865 75

Interleukin-6 (IL-6) exerts neuroprotective effects after cerebral ischaemia but can also exacerbate inflammation and induce neuronal death. The current study investigates the role of cerebral peroxisome proliferator-activated receptor(s) gamma (PPARgamma) in the regulation of IL-6 expression in the peri-infarct cortical tissue in rats exposed to focal cerebral ischaemia. Pioglitazone, a high-affinity PPARgamma ligand, was infused intracerebroventricularly (i.c.v.) via osmotic minipumps over a 5-day period before, during and 24 h or 48 h after middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion. The expression of PPARgamma and IL-6 in cortical tissue adjacent to the ischaemic core was studied 24 h and 48 h after MCAO. Pioglitazone augmented the ischaemia-induced upregulation of PPARgamma at both time points. Cerebral ischaemia substantially increased IL-6 expression in the peri-infarct cortical tissue. Twenty-four hours after MCAO, the majority of microglial cells/macrophages showed an intense IL-6 immunoreactivity. IL-6 was also localized in neurons, but the distribution of neurons positively stained for IL-6 at the border of the infarct was very heterogeneous. Pioglitazone effectively decreased the number of IL-6-immunoreactive cells and IL-6 protein levels at 24 h but not at 48 h after MCAO. Pioglitazone treatment reduced the infarct size and improved neurological functions. The present study demonstrates that cerebral PPARgamma suppresses the expression of IL-6 in ischaemic brain tissue during the initial phase of ischaemic stroke, in which the overproduction of IL-6 may aggravate neuronal damage, but not at later time points, when IL-6 promotes neuroprotection and inhibits neuronal death.
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PMID:Peroxisome proliferator-activated receptorsgamma (PPARgamma) differently modulate the interleukin-6 expression in the peri-infarct cortical tissue in the acute and delayed phases of cerebral ischaemia. 1897 94


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