Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stroke elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. Thrombolysis with tissue plasminogen activator (tPA) promotes adverse vascular events that limit the therapeutic window of stroke to three hours. Proteasome inhibitors reduce vascular thrombotic and inflammatory events, and consequently protect vascular function. The present study evaluated the neuroprotective effect of bortezomib, a potent and selective inhibitor of the proteasome, alone and in combination with delayed thrombolytic therapy on a rat model of embolic focal cerebral ischemia. Treatment with bortezomib reduces adverse cerebrovascular events including secondary thrombosis, inflammatory responses, and blood brain barrier (BBB) disruption, and hence reduces infarct volume and neurological functional deficit when administrated within 4 h after stroke onset. Combination of bortezomib and tPA extends the thrombolytic window for stroke to 6 h, which is associated with the improvement of vascular patency and integrity. Real time RT-PCR of endothelial cells isolated by laser-capture microdissection from brain tissue and Western blot analysis showed that bortezomib upregulates endothelial nitric oxide synthase (eNOS) expression and blocks NF-kappaB activation. These results demonstrate that bortezomib promotes eNOS dependent vascular protection, and reduces NF-kappaB dependent vascular disruption, all of which may contribute to neuroprotection after stroke.
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PMID:Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator. 1654 76

In this report, we provide direct demonstration that the neurotrophin nerve growth factor (NGF) is released in the extracellular space in an activity-dependent manner in its precursor form (proNGF) and that it is in this compartment that its maturation and degradation takes place because of the coordinated release and the action of proenzymes and enzyme regulators. This converting protease cascade and its endogenous regulators (including tissue plasminogen activator, plasminogen, neuroserpin, precursor matrix metalloproteinase 9, and tissue inhibitor metalloproteinase 1) are colocalized in neurons of the cerebral cortex and released upon neuronal stimulation. We also provide evidence that this mechanism operates in in vivo conditions, as the CNS application of inhibitors of converting and degrading enzymes lead to dramatic alterations in the tissue levels of either precursor NGF or mature NGF. Pathological alterations of this cascade in the CNS might cause or contribute to a lack of proper neuronal trophic support in conditions such as cerebral ischemia, seizure and Alzheimer's disease or, conversely, to excessive local production of neurotrophins as reported in inflammatory arthritis pain.
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PMID:Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. 1661 25

Thrombolysis with tissue plasminogen activator (tPA) is the only pharmacotherapy available for cerebral ischemia. However, the use of tPA can increase the risk of hemorrhage due to blood-brain barrier (BBB) breakdown. Recent evidence suggests that increased activation of matrix metalloproteinases (MMPs) may be involved in this breakdown. This study examines the temporal profile of MMP-2 and -9 following tPA administration to ischemic rats. Male Sprague-Dawley rats were randomly assigned to one of four groups (Sham-tPA; Sham-Saline; Ischemia-tPA; Ischemia-Saline; group n = 6, total N = 120). Focal embolic ischemia was induced by middle cerebral artery occlusion through injection of an autologous clot. One hour post-surgery, tPA (10 mg/kg) or saline was delivered intravenously and animals were euthanized at 3, 6, 12, or 24 h after onset of ischemia. Infarct volume was measured by TTC staining; BBB components examined immunohistochemically; and MMP activation measured by gelatin zymography. Our results show that tPA significantly reduced infarct volumes (overall infarct volume-Sham-tPA: 5.80 +/- 4.55 [mean +/- SE]; Sham-Saline: 5.00 +/- 4.23; Ischemia-tPA: 186.1 +/- 73.45; Ischemia-Saline: 284.8 +/- 88.74; all P < 0.05). Treatment with tPA was also associated with the activation of MMP-9 at 6, 12, and 24 h following ischemia. No temporal changes were observed in MMP-2 activation, although tPA administration increased its activity compared to saline treatment. Analyses of immunohistochemistry showed that destruction of components of the BBB followed MMP-9 activation. Thus, increased MMP-9 activation may, in part, be responsible for the increases in hemorrhagic transformation reported with use of tPA. Our study is the first to demonstrate the temporal profile of MMP activation following thrombolysis with tPA in a model of thrombotic focal cerebral ischemia.
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PMID:Matrix metalloproteinase activation and blood-brain barrier breakdown following thrombolysis. 1662 94

The Merci Retriever is a device used for mechanical clot extraction in cerebral arteries. It obtained US FDA clearance in August 2004 for recanalization of cerebral arteries in acute stroke. Previously, intravenous recombinant tissue plasminogen activator administered within 3 h from symptom onset was the only other FDA-approved treatment in acute stroke. Stroke from large brain artery occlusion, which has the highest morbidity and mortality rate, is inefficiently treated with intravenous recombinant tissue plasminogen activator and has a high likelihood of hemorrhagic complication. In the multicenter prospective Mechanical Embolus Removal in Cerebral Ischemia trial that led to FDA clearance, the Merci Retriever achieved 48% vessel recanalization when used within 8 h of stroke onset, and resulted in lower morbidity and mortality in revascularized patients. Clinical efficacy trials are needed to determine the place of this device in the treatment of stroke patients.
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PMID:Merci Retriever in acute stroke treatment. 1668 48

We have recently shown that melatonin decreases the late (24 hr) increase in blood-brain barrier (BBB) permeability and the risk of tissue plasminogen activator-induced hemorrhagic transformation following ischemic stroke in mice. In the study, we further explored whether melatonin would reduce postischemic neurovascular oxidative/nitrosative damage and, therefore, improve preservation of the early increase in the BBB permeability at 4 hr after transient focal cerebral ischemia for 60 min in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the beginning of reperfusion. Hydroethidine (HEt) in situ detection and immunohistochemistry for nitrotyrosine were used to evaluate postischemic accumulation in reactive oxygen and nitrogen species, respectively, in the ischemic neurovascular unit. BBB permeability was evaluated by spectrophotometric and microscopic quantitation of Evans Blue leakage. Relative to controls, melatonin-treated animals not only had a significantly reduced superoxide accumulation in neurovascular units in boundary zones of infarction, by reducing 35% and 54% cytosolic oxidized HEt in intensity and cell-expressing percentage, respectively (P < 0.001), but also exhibited a reduction in nitrotyrosine by 52% (P < 0.01). Additionally, melatonin-treated animals had significantly reduced early postischemic disruption in the BBB permeability by 53% (P < 0.001). Thus, melatonin reduced postischemic oxidative/nitrosative damage to the ischemic neurovascular units and improved the preservation of BBB permeability at an early phase following transient focal cerebral ischemia in mice. The findings further highlight the ability of melatonin in anatomical and functional preservation for the ischemic neurovascular units and its relevant potential in the treatment of ischemic stroke.
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PMID:Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood-brain barrier permeability after transient focal cerebral ischemia in mice. 1687 24

In vitro studies suggested that tissue plasminogen activator (t-PA) may aggravate ischemic injury by enhancing N-methyl-D-aspartate (NMDA) receptor signalling. It remained unclear whether NMDA signalling is also relevant for t-PA toxicity in vivo. We herein examined effects of intravenous t-PA (10 mg/kg), administered alone or in combination with the NMDA antagonist MK-801 (0.2 mg/kg), following 90 min of middle cerebral artery occlusion in mice. In our study, MK-801 alone, administered intraperitoneally, neither affected infarct volume nor brain swelling at 24 h after reperfusion. t-PA significantly increased infarct size, in accordance with previous findings. t-PA-induced ischemic injury was completely abolished and brain swelling markedly reduced when t-PA-treated animals received additional MK-801 injections. To elucidate how t-PA influences brain damage, we examined actions of t-PA on the expression of NO synthases by immunohistochemistry, showing that t-PA does not influence neuronal NO synthase, but increases inducible NO synthase in ischemic areas. The effect of t-PA on inducible NO synthase levels was completely reversed after cotreatment with MK-801. Our study provides in vivo evidence in a model of focal cerebral ischemia that t-PA-induced brain injury involves an NMDA receptor-dependent mechanism.
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PMID:Tissue plasminogen activator-induced ischemic injury is reversed by NMDA antagonist MK-801 in vivo. 1690 47

A decade after the US Food and Drug Administration (FDA) approved intravenous tissue plasminogen activator for treatment of acute ischemic stroke, the public health impact of this treatment on stroke outcome remains limited. The extremely small time window for treatment and very low recanalization rates in large artery strokes are its major shortcomings. Endovascular therapies for the treatment of acute stroke have rapidly evolved during this time period and may overcome these limitations. FDA approval of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) concentric retriever in August 2004 for the treatment of occluded brain arteries has spurred trials of newer devices for mechanical thrombolysis in acute stroke. At present, there are two major National Institutes of Health-sponsored randomized controlled trials testing endovascular treatments in acute stroke. In this article, we provide an experience-guided review of the current approach to the endovascular treatment of acute ischemic stroke and current evidence for various strategies. We first emphasize the key aspects of patient selection, including the increasingly central role of perfusion/diffusion imaging. The technical aspects of chemical, mechanical, ultrasound-based, and multimodal approaches are provided along with the authors' own experiences. Most of the endovascular modalities tested in clinical trials show recanalization rates in the range of 50% to 65%. However, no one modality is clearly superior. In practice, multimodal treatment strategy is often employed to achieve rapid recanalization of occluded cerebral vessels and minimize chances of hemorrhage. This may become the standard of care in the future.
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PMID:Acute endovascular stroke therapy. 1707 90

Acute ischemic stroke is one of the leading causes of mortality and chronic disability in the western world. Yet, despite the enormous socioeconomic burden that it imposes, therapies to combat AIS are not widely available. Moreover, revascularization of the ischemic tissue with tissue plasminogen activator, the only FDA-approved therapy for AIS, is hampered by a very narrow therapeutic time window and is only used in a minority of patients. Cerebral ischemia leads to brain damage caused by several pathologic mechanisms that can potentially be blocked by neuroprotective drugs that aim to salvage the ischemic penumbra. However, despite numerous clinical trials, no single drug candidate has proved efficacious in AIS. The current situation calls for novel therapeutic strategies to be used in acute ischemic stroke. This review surveys some of these novel and promising cutting edge therapies.
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PMID:Novel therapies for acute ischemic stroke. 1718 Aug 32

Cervicocranial arterial dissection (CCAD) occurs when there is a tear in the intimal layer of the carotid or vertebral arteries with subsequent extravasation of blood into the subintimal layers. The dissection may be extradural, intradural, or extend over both segments. The contents of the subintimal layers are highly thrombogenic, and thus, embolism, vessel stenosis, or occlusion may follow. Symptoms of dissection may be caused by local injury to the blood vessel or by ischemia to the retina or brain. Thus, dissection should always be considered in patients who present with Horner syndrome associated with ipsilateral headache, carotidynia, ocular pain, or amaurosis fugax. Rare neuro-ophthalmologic presentations of dissection include anterior and posterior ischemic optic neuropathy; central retinal artery occlusion; ophthalmic artery occlusion; transient ophthalmoparesis; and third, fourth, or sixth cranial nerve palsy. The most common serious complication of dissection is ischemic stroke. No randomized controlled trials have evaluated therapies for patients presenting with CCAD. Thus, treatment is essentially empiric and often varies by region. Medical management is first line in most patients. Given the propensity for thrombus formation and early embolization or occlusion, acute anticoagulation using intravenous heparin or low-molecular-weight heparinoids followed by short-term, dose-adjusted warfarin is the treatment of choice for most patients with extradural CCAD who present early after symptom onset. The risk of cerebral ischemia is greatest in the first few weeks after dissection; thus, it is reasonable to recommend antiplatelet agents for patients who present late and have not had evidence of ischemia. Intradural dissection is rare but is associated with a meaningful risk of subarachnoid hemorrhage (SAH). As a result, anticoagulants and antiplatelet agents should not be used if SAH is suspected or confirmed. Endovascular intervention may be necessary in a small minority of cases with recurrent events despite anticoagulation or SAH due to intradural dissection. Of special note, CCAD is not considered a contraindication for tissue plasminogen activator use in acute stroke patients who are otherwise eligible for treatment.
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PMID:Cervicocranial arterial dissection. 1728 90

FK-506 confers a neuroprotective effect and is thought to extend the time window for thrombolytic treatment of cerebral ischemia. These effects have not been assessed in an embolic stroke model. In addition, clinical studies have raised concern that FK-506 may increase the risk of hemorrhagic transformation by damaging vascular endothelial cells. We investigated whether combined administration of recombinant tissue plasminogen activator (rt-PA) and FK-506 would extend the therapeutic time window without increasing the hemorrhagic transformation in a rat embolic stroke model. Male Sprague-Dawley rats (n=66) were subjected to embolic infarction and assigned into eight groups. Six of the groups were treated with or without FK-506 (0.3 mg/kg) administration at 60 min after embolization, together with and all six groups received systemic rt-PA administration (10 mg/kg) at 60, 90, or 120 min. Two permanent ischemia groups were administered saline either with or without FK-506. Infarct and hemorrhagic volume were assessed at 24 h after embolization. Diffusion-weighted and perfusion-weighted magnetic resonance imaging (MRI) were performed in the groups administered rt-PA at 90 min and a vehicle control group to assess whether FK-506 influenced the effectiveness of MRI in revealing ischemic lesion. FK-506 extended the therapeutic time window for systemic thrombolysis compared to rt-PA alone without increasing the risk for hemorrhage. Combined therapy with FK-506 salvaged some of the MRI, revealing ischemic lesions destined to infarction in the animals treated by rt-PA alone. Single low dose of FK-506 alone did not ameliorate the embolic infarction, but it did prove effective in extending the therapeutic time windows for thrombolysis without increasing the risk of hemorrhagic transformation.
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PMID:FK-506 extended the therapeutic time window for thrombolysis without increasing the risk of hemorrhagic transformation in an embolic rat stroke model. 1731 78


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