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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article discusses the scientific and clinical targets for acute intervention including immunomodulation, the benefits of direct thrombolytic plasmin, the use of activated protein C for chronic neurodegenerative disorders, as well as strategies to modify the endothelial hemostatic-thrombotic balance to treat stroke.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Einflammatory diseases\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Esystemic atrophies\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eneurological autoimmune diseases\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ecerebrovascular disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EImmunomodulation\u003C\/h2\u003E\n         \u003Cp id=\u0022p-2\u0022\u003EInflammatory and immune mechanisms are a significant deleterious part of the stroke process. However, through immunomodulation, it is possible to attenuate brain damage following a stroke. This can be achieved through a process called mucosal tolerance, which involves the repetitive introduction of low-dose antigens either nasally or orally to tolerize regulatory T cells (Tregs). When next presented with the antigen to which they have been primed, Tregs will suppress inflammation (even if it is not caused by the antigen to which they have been tolerized) and provide local immunosuppression, a process termed \u201cbystander suppression.\u201d\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EJohn Hallenbeck, MD, National Institutes of Health, Bethesda, MD, described current research with E-selectin, a cell adhesion molecule that is only expressed on endothelial cells when they are becoming activated. The local release of the cytokines IL-1 and TNF by the inflamed cells induces the expression of E-selectin on the endothelial cells of nearby blood vessels. Dr. Hallenbeck\u0027s previous research showed that E-selectin prevented spontaneous ischemic and hemorrhagic strokes in spontaneously hypertensive, genetically stroke-prone rats compared with controls [Takeda H et al. \u003Cem\u003EStroke\u003C\/em\u003E 2002], and further, mucosal tolerance to E-selectin significantly reduced infarct volume following permanent middle cerebral artery occlusion in these animals [Chen Y et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2003].\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EHis current research in a vascular cognitive impairment model (common carotid occlusion) showed that E-selectin-tolerized animals have significantly less learning impairment compared with controls. Dr. Hallenbeck\u0027s research has also shown that mucosal tolerance to E-selectin increases Tregs in peri-infarct regions after stroke, promotes the survival of migrating neuroblasts and newly generated neurons, and can suppress a Th-17 (T cells that produce IL-17)-driven autoimmune disease. With this knowledge, Dr. Hallenbeck\u0027s team hopes to begin safety trials that test immunomodulation as a tool for the prevention of stroke.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EPlasmin\u003C\/h2\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThere are two types of thrombolytics, indirect and direct. Indirect (tPA, SK, UK, reteplase, etc) convert plasminogen to plasmin by way of an activator. Direct (plasmin, mutant derivatives, and snake venom extracts such as alfimeprase) degrade fibrin directly without the need for a precursor. Although plasminogen activators are effective for dissolving thrombi, their use is associated with an increased risk of bleeding, including intracranial hemorrhage (about 1% of patients), that can complicate regional as well as systemic therapy.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EVictor J. Marder, MD, David Geffen School of Medicine, Los Angeles, CA, discussed the benefits of the direct thrombolytic plasmin. Plasmin is inhibited by antiplasmin in the general circulation; thus, it is never administered systematically because it will be neutralized and never reach the thrombus. However, administered locally, it dissolves the thrombus with no risk of ancillary bleeding, while providing a significant safety margin.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EIn a middle cerebral artery thrombo-occlusion model in rabbits, thrombolysis\/reperfusion was achieved in 3 of 3 rabbits that were successfully administered plasmin by interarterial infusion [Jahan R et al. \u003Cem\u003EStroke\u003C\/em\u003E 2001]. In a phase 1 clinical trial, plasmin produced effective thrombolysis (\u0026gt;75%) at 24 mg with no major bleeding [Shlansky-Goldberg et al. \u003Cem\u003EJ Thromb Haemost\u003C\/em\u003E in press]. Plasmin is undergoing further testing in the Plasmin Revascularization for the Ischemic Lower Extremity (PRIORITY) trial.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EDr. Marder believes that plasmin is the ideal agent for catheter-delivered thrombolysis in that it causes less bleeding than tPA, is likely superior to tPA for lysis of plasminogen-poor thrombi, and has a highly favorable benefit-to-risk ratio.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EActivated Protein C (APC)\u003C\/h2\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EBerislav Zlokovic, MD, University of Rochester Medical Center, Rochester, NY, discussed the need for new therapeutic approaches that are directed at the blood-brain barrier and other non-neuronal cells for chronic neurodegenerative disorders. Activated protein C (APC) is an antithrombotic, anti-inflammatory, and profibrinolytic agent that first drew attention as a successful treatment for sepsis in the PROWESS study [Bernard GR et al. \u003Cem\u003ENEJM\u003C\/em\u003E 2001]. APC reduced the relative risk of death of patients with severe sepsis by 19.4%. In mouse cortical neurons, APC blocks apoptosis that is induced by N-methyl-D-aspartate (NMDA) and staurosporine, demonstrating direct protection of neurons and suggesting that it might be a useful treatment for amyotrophic lateral sclerosis (ALS), Alzheimer disease, and ischemic stroke [Guo H et al. \u003Cem\u003ENeuron\u003C\/em\u003E 2004]. APC also activates anti-apoptotic pathways in brain endothelium that is affected by ischemia or tPA in cultured brain endothelium and \u003Cem\u003Ein vivo\u003C\/em\u003E (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). APC is currently being investigated in patients with acute ischemic stroke in the Activated Protein C in Acute Stroke Trial.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/5\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Activated Protein C (APC): Modeling Stroke.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-525108971\u0022 data-figure-caption=\u0022Activated Protein C (APC): Modeling Stroke.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/5\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/5\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/5\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11013\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-10\u0022 class=\u0022first-child\u0022\u003EActivated Protein C (APC): Modeling Stroke.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EA more recent study [Cheng T et al. \u003Cem\u003ENature Medicine\u003C\/em\u003E 2003] showed that APC inhibits a prohemorrhagic, tPA-induced, NF-kappaB-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium \u003Cem\u003Ein vivo\u003C\/em\u003E and \u003Cem\u003Ein vitro\u003C\/em\u003E by acting through protease-activated receptor 1. This suggests that APC may improve thrombolytic therapy for stroke in part by reducing tPA-mediated hemorrhage.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EDr. Zlokovic is planning phase 2\/3 clinical trials that look at the angiogenesis, neurogenesis, neuronal re-wiring, vascular remodeling, and metabolic coupling properties of APC.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-4\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EModulating Endothelial Cell Anticoagulant Properties\u003C\/h2\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EMark Fisher, MD, University of California, Irvine, CA, discussed strategies to modify the endothelial hemostatic-thrombotic balance as a way to treat stroke. Endothelial cells express a variety of pro- and antithrombotic properties. The antithrombotic properties include the production of prostacyclin, thrombomodulin, nitric oxide, and tPA. Prothrombotic factors include tissue factor, Von Willebrand factor, and plasminogen activator (PAI-1).\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EReferencing previous research, Dr. Fisher pointed out that thrombomodulin can transform thrombin\u0027s usual procoagulant effects into anticoagulant function via the thrombin-thrombomodulin complex, which activates protein C. Thrombomodulin is ubiquitous in endothelial cells throughout the systemic microcirculation but is reduced at the blood-brain barrier; areas that are predisposed to lacunar infarction have a particularly low abundance of thrombomodulin [Ishii H et al. \u003Cem\u003EBlood\u003C\/em\u003E 1986; Wong VL et al. \u003Cem\u003EBrain Res\u003C\/em\u003E 1991]. Thrombomodulin is easily demonstrable in microvasculature of brain tumors, in contrast to microvessels of normal brain [Isaka T et al. \u003Cem\u003EActa Neuropathol\u003C\/em\u003E 1994], and normal brain capillary endothelial cells rarely express tPA [Levin and Del Zoppo. 1994]. This underexpression of anticoagulant factors by brain microvascular endothelial cells, coupled with abundant expression of tissue factor by blood-brain barrier astrocytes, may predispose to ischemia in prothrombotic or inflammatory conditions.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EDr. Fisher offered 3 strategies to modify endothelial anticoagulant function that included using statins, using phosphodiesterase inhibitors, and inhibiting the renin-angiotensin system. Manipulating the prothrombotic properties of the brain may offer protection against infarction.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EHe concluded by saying that the brain contains procoagulant properties based in the microvasculature, which presents multiple potential therapeutic targets to alter endothelial anticoagulant function as stroke intervention.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2008 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/8\/1\/5.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmgpp\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmgpp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}