G J del Zoppo

Azienda Ospedaliera Carlo Poma Mantova, Mantoue, Lombardy, Italy

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Publications (165)1099.24 Total impact

  • 08/2014; 384(9944):661–662.
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    ABSTRACT: Malignant infarction is characterized by the formation of cerebral edema, and medical treatment is limited. Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema. We previously reported feasibility of the GAMES-Pilot study, a two-center prospective, open label, phase IIa trial of 10 subjects at high risk for malignant infarction based on diffusion weighted imaging (DWI) threshold of 82 cm(3) treated with RP-1127 (glyburide for injection). In this secondary analysis, we tested the hypothesis that RP-1127 may be efficacious in preventing poor outcome when compared to controls. Controls suffering large hemispheric infarction were obtained from the EPITHET and MMI-MRI studies. We first screened subjects for controls with the same DWI threshold used for enrollment into GAMES-Pilot, 82 cm(3). Next, to address imbalances, we applied a weighted Euclidean matching. Ninety day mRS 0-4, rate of decompressive craniectomy, and mortality were the primary clinical outcomes of interest. The mean age of the GAMES cohort was 51 years and initial DWI volume was 102 ± 23 cm(3). After Euclidean matching, GAMES subjects showed similar NIHSS, higher DWI volume, younger age and had mRS 0-4-90 % versus 50 % in controls p = 0.049; with a similar trend in mRS 0-3 (40 vs. 25 %; p = 0.43) and trend toward lower mortality (10 vs. 35 %; p = 0.21). In this pilot study, RP-1127-treated subjects showed better clinical outcomes when compared to historical controls. An adequately powered and randomized phase II trial of patients at risk for malignant infarction is needed to evaluate the potential efficacy of RP-1127.
    Neurocritical Care 03/2014; · 3.04 Impact Factor
  • Alfonso Ciccone, Gregory J Del Zoppo
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    ABSTRACT: The perceived advantages of endovascular treatment for acute ischemic stroke in terms of recanalization, the multimodal and targeted approaches, and perhaps the more permissive rules on devices than on medications for their licensing favored the assumption that endovascular treatment is superior to intravenous thrombolysis for acute treatment of ischemic stroke, and its adoption in more advanced stroke centers. However, this assumption has been questioned by recent clinical trial experience showing that endovascular treatment is not superior to intravenous thrombolysis. The new evidence has changed the perception and the importance of conducting randomized trials in this area. This summary examines the background and outcomes of the latest experience with endovascular techniques in acute stroke treatment based on historical data. The new challenge is how to study the latest generation of devices called stent retrievers, which are faster in recanalizing and easier to use, in selected patients with acute ischemic stroke. In the meantime, the available evidence does not provide support for the use of endovascular treatment of acute ischemic stroke in clinical practice.
    Current Neurology and Neuroscience Reports 01/2014; 14(1):416. · 3.78 Impact Factor
  • Gregory J Del Zoppo, Yoshikane Izawa, Brian T Hawkins
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    ABSTRACT: Modulation of coagulation has been successfully applied to ischemic disorders of the central nervous system (CNS). Some components of the coagulation system have been identified in the CNS, yet with limited exception their functions have not been clearly defined. Little is known about how events within the cerebral tissues affect hemostasis. Nonetheless, the interaction between cerebral cells and vascular hemostasis and the possibility that endogenous coagulation factors can participate in functions within the neurovascular unit provide intriguing possibilities for deeper insight into CNS functions and the potential for treatment of CNS injuries. Here, we consider the expression of coagulation factors in the CNS, the coagulopathy associated with focal cerebral ischemia (and its relationship to hemorrhagic transformation), the use of recombinant tissue plasminogen activator (rt-PA) in ischemic stroke and its study in animal models, the impact of rt-PA on neuron and CNS structure and function, and matrix protease generation and matrix degradation and hemostasis. Interwoven among these topics is evidence for interactions of coagulation factors with and within the CNS. How activation of hemostasis occurs in the cerebral tissues and how the brain responds are difficult questions that offer many research possibilities.
    Seminars in Thrombosis and Hemostasis 11/2013; 39(8):856-75. · 4.22 Impact Factor
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    ABSTRACT: The sulfonylurea receptor 1 (Sur1)-transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and "accidental necrotic cell death." Blockade of Sur1 using glibenclamide has been studied in different types of rat models of stroke: (i) in conventional non-lethal models (thromboembolic, 1-2 h temporary, or permanent middle cerebral artery occlusion), glibenclamide reduces brain swelling and infarct volume and improves neurological function; (ii) in lethal models of malignant cerebral edema, glibenclamide reduces edema, brain swelling, and mortality; (iii) in models with rtPA, glibenclamide reduces swelling, hemorrhagic transformation, and death. Retrospective studies of diabetic patients who present with stroke have shown that those whose diabetes is managed with a sulfonylurea drug and who are maintained on the sulfonylurea drug during hospitalization for stroke have better outcomes at discharge and are less likely to suffer hemorrhagic transformation. Here, we provide a comprehensive review of the basic science, preclinical experiments, and retrospective clinical studies on glibenclamide in focal cerebral ischemia and stroke. We also compare the preclinical work in stroke models to the updated recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR). The findings reviewed here provide a strong foundation for a translational research program to study glibenclamide in patients with ischemic stroke.
    Neurocritical Care 10/2013; · 3.04 Impact Factor
  • International Journal of Stroke 06/2013; 8:278-283. · 2.75 Impact Factor
  • Anesthesiology 05/2013; · 5.16 Impact Factor
  • Gregory J Del Zoppo
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    ABSTRACT: Appropriate acute treatment with plasminogen activators (PAs) can significantly increase the probability of minimal or no disability in selected ischemic stroke patients. There is a great deal of evidence showing that intravenous recombinant tissue PAs (rt-PA) infusion accomplishes this goal, recanalization with other PAs has also been demonstrated in the development of this treatment. Recanalization of symptomatic, documented carotid or vertebrobasilar arterial territory occlusions have also been achieved by local intra-arterial PA delivery, although only a single prospective double-blinded randomized placebo-controlled study has been reported. The increase in intracerebral hemorrhage with these agents by either delivery approach underscores the need for careful patient selection, dose-appropriate safety and efficacy, proper clinical trial design, and an understanding of the evolution of cerebral tissue injury due to focal ischemia. Principles underlying the evolution of focal ischemia have been expanded by experience with acute PA intervention. Several questions remain open that concern the manner in which PAs can be applied acutely in ischemic stroke and how injury development can be limited.
    Seminars in Thrombosis and Hemostasis 03/2013; · 4.22 Impact Factor
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    ABSTRACT: Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.Journal of Cerebral Blood Flow & Metabolism advance online publication, 27 March 2013; doi:10.1038/jcbfm.2013.45.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2013; · 5.46 Impact Factor
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    Acta Neuropathologica 03/2013; 125(3):313-6. · 9.73 Impact Factor
  • Brian T Hawkins, Yu-Huan Gu, Yoshikane Izawa, Gregory J Del Zoppo
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    ABSTRACT: Cerebral edema is a serious complication of ischemic brain injury. Cerebral edema includes accumulation of extracellular fluid due to leakage of the brain's microvessel permeability barrier, and swelling of astrocytes as they absorb water from the extracellular space. Expression of matrix adhesion receptors in brain microvessels decreases in ischemic stroke; this contributes to increased microvessel permeability and detachment of astrocytes from the extracellular matrix (ECM). Since loss of the astrocyte adhesion receptor dystroglycan has been associated with disrupted polarization of ion and water channels, we hypothesized that adhesion of astrocytes to the ECM contributes to regulation of water uptake, and that disruption of matrix adhesion impairs the ability of astrocytes to direct water transport. To test this hypothesis, the capacity of astrocytes to take up water was measured using a fluorescence self-quenching assay under both oxygen/glucose deprivation (OGD) and direct antibody-mediated blockade of α-dystroglycan. Both conditions decreased the rate of water uptake. Moreover, inhibiting proteolytic cleavage of dystroglycan that occurs in OGD abrogated the effect of OGD, but not direct blockade of α-dystroglycan, indicating that interfering with dystroglycan-matrix binding itself affects water uptake. Activation of extracellular signal-related kinase (ERK) by OGD was dependent on α-dystroglycan binding, and inhibition of ERK activity with U0126 abrogated the loss of water uptake following OGD. These studies demonstrate for the first time that water uptake in astrocytes is regulated by dystroglycan-dependent signaling associated with matrix adhesion. This presents a novel potential approach to the treatment of cerebral edema.
    Brain research 02/2013; · 2.46 Impact Factor
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    ABSTRACT: The brain is in many ways an immunologically and pharmacologically privileged site. The blood-brain barrier (BBB) of the cerebrovascular endothelium and its participation in the complex structure of the neurovascular unit (NVU) restrict access of immune cells and immune mediators to the central nervous system (CNS). In pathologic conditions, very well-organized immunologic responses can develop within the CNS, raising important questions about the real nature and the intrinsic and extrinsic regulation of this immune privilege. We assess the interactions of immune cells and immune mediators with the BBB and NVU in neurologic disease, cerebrovascular disease, and intracerebral tumors. The goals of this review are to outline key scientific advances and the status of the science central to both the neuroinflammation and CNS barriers fields, and highlight the opportunities and priorities in advancing brain barriers research in the context of the larger immunology and neuroscience disciplines. This review article was developed from reports presented at the 2011 Annual Blood-Brain Barrier Consortium Meeting.Journal of Cerebral Blood Flow & Metabolism advance online publication, 17 October 2012; doi:10.1038/jcbfm.2012.153.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 10/2012; · 5.46 Impact Factor
  • Gregory J Del Zoppo
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    ABSTRACT: The Nobel laureate Max Delbrück often said that it is the crossover between disciplines where advances are possible in science. This certainly has been true for our understanding of the vascular biology of the central nervous system in the setting of ischemic stroke. The ability to cross the boundaries of hemostasis, neurology, hematology, and neuroscience has facilitated our research direction to define the relation of the microvasculature to neuron function. Work begun with the clinical scientific exploration of the contributions of arterial thrombosis to the acute injury processes initiated by focal cerebral ischemia has led to an increased understanding of the effects of ischemia on microvessel integrity.
    Stroke 10/2012; · 6.16 Impact Factor
  • Gregory J Del Zoppo, Andrei V Alexandrov
    Annals of the New York Academy of Sciences 09/2012; 1268(1):vii-viii. · 4.38 Impact Factor
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    Gregory J Del Zoppo
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    ABSTRACT: With the demonstration that acute recanalization of obstructed symptomatic cerebral arteries during ischemic stroke can result in substantial improvement in clinical outcome, the variability in clinical responses, and in hemorrhagic transformation, requires attention. This short review addresses the effect of aging and amyloid deposition disease on microvessel integrity, interactions within the neurovascular unit, cerebral tissue susceptibility to ischemic injury, and postischemic inflammation, and ultimately on the outcomes and safety of acute recanalization during ischemic stroke. Microvessels and neighboring neurons respond simultaneously to focal ischemia. The cellular components and matrix barriers of the neurovascular unit all respond to ischemia; however, their coordinate interactions are not understood. Furthermore, there is little known about the cell-cell and cell-matrix interactions within the unit, or about the effect of β-amyloid on microvessel responses during ischemia. These considerations indicate the need for a coordinated research effort to understand the origins of the variability in recanalization outcome.
    Annals of the New York Academy of Sciences 09/2012; 1268(1):127-33. · 4.38 Impact Factor
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    ABSTRACT: Recombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated soon after acute ischaemic stroke in randomised trials, but licensing is restrictive and use varies widely. The IST-3 trial adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic stroke in an updated systematic review and meta-analysis. We searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke. In up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0-2) at final follow-up (1611/3483 [46·3%] vs 1434/3404 [42·1%], OR 1·17, 95% CI 1·06-1·29; p=0·001), absolute increase of 42 (19-66) per 1000 people treated, and favourable outcome (mRS 0-1) absolute increase of 55 (95% CI 33-77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0-2, 365/896 [40·7%] vs 280/883 [31·7%], 1·53, 1·26-1·86, p<0·0001), absolute benefit of 90 (46-135) per 1000 people treated, and mRS 0-1 (283/896 [31·6%] vs 202/883 [22·9%], 1·61, 1·30-1·90; p<0·0001), absolute benefit 87 (46-128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 [8·9%] vs 174/2728 [6·4%], 1·44, 1·18-1·76; p=0·0003), but by final follow-up the excess was no longer significant (679/3548 [19·1%] vs 640/3464 [18·5%], 1·06, 0·94-1·20; p=0·33). Symptomatic intracranial haemorrhage (272/3548 [7·7%] vs 63/3463 [1·8%], 3·72, 2·98-4·64; p<0·0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early. The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke. UK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital.
    The Lancet 05/2012; 379(9834):2364-72. · 39.06 Impact Factor
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    ABSTRACT: Hemorrhage and edema accompany evolving brain tissue injury after ischemic stroke. In patients, these events have been associated with metalloproteinase (MMP)-9 in plasma. Both the causes and cellular sources of MMP-9 generation in this setting have not been defined. MMP-2 and MMP-9 in nonhuman primate tissue in regions of plasma leakage, and primary murine microglia and astrocytes, were assayed by immunocytochemistry, zymography, and real-time RT-PCR. Ischemia-related hemorrhage was associated with microglial activation in vivo, and with the leakage of plasma fibronectin and vitronectin into the surrounding tissue. In strict serum-depleted primary cultures, by zymography, pro-MMP-9 was generated by primary murine microglia when exposed to vitronectin and fibronectin. Protease secretion was enhanced by experimental ischemia (oxygen-glucose deprivation, OGD). Primary astrocytes, on each matrix, generated only pro-MMP-2, which decreased during OGD. Microglia-astrocyte contact enhanced pro-MMP-9 generation in a cell density-dependent manner under normoxia and OGD. Compatible with observations in a high quality model of focal cerebral ischemia, microglia, but not astrocytes, respond to vitronectin and fibronectin, found when plasma extravasates into the injured region. Astrocytes alone do not generate pro-MMP-9. These events explain the appearance of MMP-9 antigen in association with ischemia-induced cerebral hemorrhage and edema.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2012; 32(5):919-32. · 5.46 Impact Factor
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    ABSTRACT: Glia synthesize, package, and secrete several species of matrix proteases, including the gelatinases (pro-)MMP-2 and (pro-)MMP-9. In appropriate settings (e.g., experimental ischemia), these MMPs can be assayed from cerebral tissues or from astrocytes and microglia in culture by enzymatic substrate-dependent assays and by gelatin-based zymography. We describe the methodologies for the sensitive quantitative development of the inactive and active forms of both MMP-2 and MMP-9 from tissues and cells, by means of lysis of the collagen substrate in collagen-impregnated gel electropheresis by the zymogen and active gelatinases. These methodologies are a refinement of those used commonly, with instructions to increase sensitivity. Serious and often overlooked issues regarding sources of sample contamination and elements confounding the MMP band development and their interpretation are discussed.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 814:221-33. · 1.29 Impact Factor
  • Gregory J Del Zoppo
    Rinshō shinkeigaku = Clinical neurology. 01/2012; 52(11):826.
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    Gregory J del Zoppo, Misha Eliasziw
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    ABSTRACT: The presence of atrial fibrillation significantly increases the risk and burden of thromboembolic stroke.(1) Warfarin is the reference standard treatment for the primary prevention of embolic stroke during atrial fibrillation.(2) However, the long-term use of warfarin has its limitations. Although guidelines suggest a target international normalized ratio (INR) of 2.5 (range, 2.0 to 3.0) for this indication,(2) only about 60% of patients have an INR within the recommended range at a given time in usual clinical practice. This is the reason that is most often given for the search for other oral antithrombotic agents that could be simpler to manage . . .
    New England Journal of Medicine 08/2011; 365(10):952-3. · 51.66 Impact Factor

Publication Stats

11k Citations
1,099.24 Total Impact Points

Institutions

  • 2014
    • Azienda Ospedaliera Carlo Poma Mantova
      Mantoue, Lombardy, Italy
  • 2008–2014
    • University of Washington Seattle
      • • Department of Neurology
      • • Division of Hematology
      • • Department of Medicine
      Seattle, Washington, United States
  • 2012
    • University of California, San Diego
      • Department of Pediatrics
      San Diego, CA, United States
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 1988–2012
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      La Jolla, California, United States
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
  • 2011
    • The University of Calgary
      • Department of Community Health Sciences
      Calgary, Alberta, Canada
  • 2009
    • The University of Edinburgh
      • Division of Clinical Neurosciences
      Edinburgh, SCT, United Kingdom
  • 2007
    • Duke University Medical Center
      Durham, North Carolina, United States
  • 2001
    • National Institutes of Health
      • Branch of Stroke and Ischemia
      Bethesda, MD, United States
  • 1999–2000
    • Ludwig-Maximilian-University of Munich
      • Department of Neurology
      München, Bavaria, Germany
  • 1996
    • CSU Mentor
      Long Beach, California, United States
    • Rowe Neuroscience Institute
      Lenexa, Kansas, United States
  • 1994
    • Henry Ford Hospital
      • Department of Neurology
      Detroit, Michigan, United States
  • 1986
    • University Hospital RWTH Aachen
      • Department of Neurology
      Aachen, North Rhine-Westphalia, Germany