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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment of ischemic strokes is limited to prophylactic agents that block the coagulation cascade. Here, we show that cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, protect against cerebral injury by a previously unidentified mechanism involving the selective up-regulation of endothelial NO synthase (eNOS). Prophylactic treatment with HMG-CoA reductase inhibitors augments cerebral blood flow, reduces cerebral infarct size, and improves neurological function in normocholesterolemic mice. The up-regulation of eNOS by HMG-CoA reductase inhibitors is not associated with changes in serum cholesterol levels, but is reversed by cotreatment with L-mevalonate and by the downstream isoprenoid, geranylgeranyl pyrophosphate and not by farnesyl pyrophosphate. The blood flow and neuroprotective effects of HMG-CoA reductase inhibitors are completely absent in eNOS-deficient mice, indicating that enhanced eNOS activity by HMG-CoA reductase inhibitors is the predominant if not the only mechanism by which these agents protect against cerebral injury. Our results suggest that HMG-CoA reductase inhibitors provide a prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia.
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PMID:Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. 967 73

A considerable number of large scale clinical trials provide clear evidence that cholesterol lowering is one of the most important risk-reduction strategies for secondary and primary prevention of coronary artery disease. Unlike the older studies with fibrates, the most recent trials of cholesterol-lowering therapies with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have clearly shown that their use can reduce coronary artery disease and total mortality as well as the need for expensive hospitalization and revascularization procedures. Studies such as the Scandinavian Simvastatin Survival Study (4S), the West of Scotland Coronary Prevention Study (WOS), the Cholesterol and Recurrent Events (CARE) trial and most recently the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) as well as numerous other investigations, have established that decreasing elevated levels of low-density lipoprotein (LDL) cholesterol will result in a reduction in risk of coronary artery disease. In addition, HMG-CoA reductase inhibition reduces the risk for cerebral ischemia. Recent data indicate that less than half of patients with coronary artery disease receive cholesterol-lowering therapy, and few meet the LDL-cholesterol goal. Therefore clinicians treating coronary artery disease need to emphasize secondary prevention and recognize the key role of cholesterol-lowering therapy. The challenge for clinicians is to apply the important lessons learned from these clinical trials to an "evidence-based" patient care.
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PMID:[Prevention of coronary heart disease--"evidence-based medicine" of antilipemic therapy]. 1009 8

Endothelial-derived nitric oxide (NO) is an important mediator of vascular function. Clinical studies indicate that HMG-CoA reductase inhibitors (statins) improve endothelial function and reduce the incidence of stroke and myocardial infarction. Treatment of human endothelial cells with statins increased the expression of endothelial NO synthase (eNOS) protein and mRNA expression. Statins increased eNOS mRNA half-life but did not change eNOS gene transcription. Inhibition of mevalonate synthesis by statins not only blocks the formation of cholesterol but also of isoprenoids. The upregulation of eNOS expression by statins was independent of cholesterol but mediated via the inhibition of the isoprenoid geranylgeraniol, whereas farnesiol had no effect on eNOS. Immunoblot analyses, (35S)-GTP gamma S-binding assays and transfection studies revealed that statins upregulate eNOS expression by blocking the geranylgeranylation of the GTPase Rho which is necessary for its membrane-associated activity. Studies with mice showed, that statin treatment upregulates eNOS expression and function independent of serum cholesterol levels. Prophylactic treatment with statins augmented cerebral blood flow and reduced cerebral infarcts in normocholesterolemic mice. These effects of statins were completely absent in eNOS-deficient mice indicating that enhanced eNOS activity by statins is the predominant mechanism by which these agents protect against cerebral injury. Our results suggest that statins provide a novel prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia. Upregulation of eNOS by inhibiting Rho may provide a new pharmacologic target for the treatment of arteriosclerosis, pulmonary hypertension, and heart failure.
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PMID:[Regulation of endothelial NO production by Rho GTPase]. 1037 57

Cerebral blood flow is regulated by endothelium-derived nitric oxide (NO), and endothelial NO synthase-deficient (eNOS-deficient; eNOS(-/-)) mice develop larger cerebral infarctions following middle cerebral artery (MCA) occlusion. We report that disruption of Rho-mediated endothelial actin cytoskeleton leads to the upregulation of eNOS expression and reduces the severity of cerebral ischemia following MCA occlusion. Mice treated with the Rho inhibitor Clostridium botulinum C3 transferase (10 microgram/d) or the actin cytoskeleton disrupter cytochalasin D (1 mg/kg) showed a two- to fourfold increase in vascular eNOS expression and activity. This increase in eNOS expression was not due to increases in eNOS gene transcription, but to prolongation of eNOS mRNA half-life from 10 +/- 3 hours to 24 +/- 4 hours. Indeed, endothelial cells overexpressing a dominant-negative Rho mutant (N19RhoA) exhibited decreased actin stress fiber formation and increased eNOS expression. Inhibition of vascular Rho guanosine-5'-triphosphate binding activity by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin increased cerebral blood flow to ischemic regions of the brain, and mice treated with simvastatin, C3 transferase, or cytochalasin D showed smaller cerebral infarctions following MCA occlusion. No neuroprotection was observed with these agents in eNOS(-/-) mice. These findings suggest that therapies which target the endothelial actin cytoskeleton may have beneficial effects in ischemic stroke.
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PMID:Neuroprotection mediated by changes in the endothelial actin cytoskeleton. 1088 44

HMG-CoA reductase inhibitors (statins) are cholesterol-lowering drugs and reduce the risk of myocardial infarction and stroke. In this study we investigated whether rosuvastatin, a new, potent HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide (NO) expression and activity and protects from cerebral ischaemia in mice. Endothelial cells in culture and 129/SV mice were chronically treated with rosuvastatin. The expression and activity of endothelial NO synthase (eNOS) was determined by reverse-transcriptase polymerase chain reaction (RT-PCR), Western blotting and arginine-citrulline assays. Cerebral ischaemia was induced by occlusion of the middle cerebral artery (MCAo) for 2 h and infarct size was determined after 22 h of reperfusion. Treatment of endothelial cells with rosuvastatin concentration- and time-dependently upregulated eNOS mRNA and protein expression. In aortas of 129/SV wild-type mice, treatment with 0.2, 2, and 20 mg kg(-1) rosuvastatin subcutaneously (s.c.) for 10 days significantly upregulated eNOS mRNA by 50, 142, and 205%, respectively. NOS activity was significantly increased by 75, 145, and 320%, respectively. Stroke volume after 2-h MCAo was reduced by 27, 56, and 50% (for 0.2, 2 and 20 mg kg(-1), respectively). Serum cholesterol and triglygeride levels were not significantly lowered by the treatment. The novel HMG-CoA reductase inhibitor rosuvastatin dose-dependently upregulates eNOS expression and activity and protects from cerebral ischaemia in mice. The effects are independent of changes in cholesterol levels and are equivalent or even superior to the protective effects by simvastatin and atorvastatin in this animal model.
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PMID:Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. 1203 49

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, reduce the incidence of strokes and reduce infarct volume after cerebral ischemia in mice. Excitoxicity caused by overstimulation of glutamate receptors is a major cause of neuronal death after an ischemic brain insult. Experiments presented here explored whether statins protect cultured neurons from excitotoxic death caused by the glutamate receptor agonist NMDA. Treatment with statins preserved NMDA receptor-expressing cortical neurons and potently and substantially reduced lactate dehydrogenase release caused by exposure of embryonic mouse neocortical cultures to NMDA. The rank order of neuroprotective potency was rosuvastatin = simvastatin > atorvastatin = mevastatin > pravastatin, which is similar to the known rank order of potency for inhibition of the HMG-CoA reductase enzyme. Resistance of cultures to NMDA excitotoxicity developed after several days of statin exposure. Neuroprotection by rosuvastatin was coincident with a decrease in cell sterols and occurred with a similar potency as inhibition of cholesterol biosynthesis. Neuroprotection was substantially attenuated by cotreatment with either mevalonate or cholesterol and was mimicked by acute treatment with the cholesterol-extracting agent beta-cyclodextrin, suggesting that neuroprotection was mediated by depletion of a cellular pool of cholesterol because of the inhibition of cholesterol biosynthesis. These results suggest the possibility that, in addition to effects on cerebrovascular function, statins have the potential to render cortical neurons more resistant to NMDA-induced excitotoxic death as a result of changes in cell cholesterol homeostasis.
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PMID:3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity. 1465 68

Nitric oxide (NO) generated by endothelial NO synthase (eNOS) plays a crucial role in vascular function and homeostasis. NO possesses vasodilatory, anti-inflammatory, antithrombotic and antiproliferative properties. Augmentation of NO production increases cerebral blood flow, which can lead to neuroprotection during brain ischaemia. Several modalities that upregulate eNOS expression and/or activity have recently been identified, including HMG-CoA reductase inhibitors (statins), steroid hormones, nutrients and physical activity. They all increase NO bioavailability, leading to enhanced cerebral blood flow and protection from ischaemic stroke. Thus, therapeutic modalities that target eNOS not only serve as preventive measures to reduce stroke incidence but also could represent novel treatment strategies for reducing brain injury during cerebral ischaemia.
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PMID:Targeting eNOS for stroke protection. 1511 Oct 11

We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can prevent the damage of interneurons in the hippocampus after cerebral ischemia. Thus, our study provides valuable information for the pathogenesis after cerebral ischemia.
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PMID:Alterations of interneurons of the gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin. 1597 Sep 48

Treatment with statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) reduces the risk of ischemic stroke among patients with increased risk of vascular disease. Recent experimental data point to neuroprotective properties of statins in acute cerebral ischemia. There is a proven link between bioavailability of nitric oxide and the activity of statins and ischemic stroke. Due to their ability to up-regulate nitric oxide synthase, statins have been considered in the therapy of a number of the central nervous system disorders, including cerebral ischemia, Alzheimer's disease, Parkinson's disease, tumors, and trauma. It has been claimed that they suppress inflammatory response and secondary injury after acute ischemia.
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PMID:Neuroprotective properties of statins. 1622 38

Dyslipemia is a clear risk factor (RF) for ischemic heart disease and peripheral artery disease, but its relation with ischemic stroke (IS) is not so clear. HMG-CoA reductase inhibitor drugs or statins (simvastatin, atorvastatin, pravastatin) reduce the relative risk of IS by between 18 and 51% in patients with IHD, in patients with high vascular disease risk and in hypertensive patients with other RFs, acute coronary syndrome, and type 2 diabetes mellitus. According to the guidelines for use, statins are indicated in the majority of patients with IS since the risk is equivalent to that of IHD or high vascular disease risk. In view of the existing clinical evidence of benefit, it would not seem unreasonable to proceed with treatment of patients using statins while awaiting specific studies justifying their use. The non-lipid-lowering mechanisms of the statins and results of studies, such as the Heart Protection Study, provide evidence for widening the indications of statins beyond the prevention of dyslipemia, as a new therapeutic approach in the prevention of IS in patients with plasma levels of total cholesterol or low density lipoproteins currently considered within the normal distribution. The neuroprotective role, which these drugs may play in the acute phase of cerebral ischemia, remains to be clarified, but very recent evidence suggests that such patients may also benefit.
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PMID:Lipids and stroke: the opportunity of lipid-lowering treatment. 1632 54


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