The overall objectives of this proposal are to examine the contribution of acute microvascular occlusions in the lenticulostriate (LSA) territory to the extent of cerebral ischemia following acute middle cerebral artery (MCA) stroke in a non-human primate model and to assess the mechanism(s) by which those occlusions are generated. The hypotheses to be tested state i) that LSA microvascular occlusions are secondary to the adherence of (and vascular obstruction by) PMN leukocytes and/or tissue factor (TF)-mediated stasis thrombosis and ii) that established monoclonal antibodies (MoAb) against leukocyte adherence and TF activity will decrease occlusion numbers and infarction volume, and improve neurological outcome. The finding of occlusions containing blood elements in the microcirculation of-the LSA territory following MCA occlusion and subsequent reperfusion in the primate acute stroke model suggests a pathogenesis for the """"""""no- flow"""""""" phenomenon in focal cerebral ischemia. Measures which reduce the extent of this phenomenon in cerebral ischemia may reduce the region of focal cerebral ischemia and improve neurological recovery. Heretofore, this concept has not been testable. The mechanism(s) of microvascular occlusion formation as defined by the ability of MoAb to inhibit occlusion formation, and the neurological consequences of these interventions will be developed in stages: i) the presence of PMN leukocytes in the LSA microvasculature will be identified and quantitated by india ink/glutaraldehyde/light microscopy and the vascular PMN leukocyte and platelet morphology will be defined by electron microscopy in short-term () hour) experiments; ii) the development of LSA microvascular occlusions will be monitored by vascular occlusion score and by IIIIn platelet deposition in the ischemic corpora striata of intact formalin-fixed brain by gamma-camera imaging in short-term (5 hour) experiments; and iii) the ability of microvascular occlusion inhibition by MoAb to decrease infarction volume and improve functional outcome will be assessed in long-term (14 day) experiments in the primate model. This approach may have significant consequences for acute stroke patient management.
| Del Zoppo, Gregory J (2013) Toward the neurovascular unit. A journey in clinical translation: 2012 Thomas Willis Lecture. Stroke 44:263-9 |
| Muldoon, Leslie L; Alvarez, Jorge I; Begley, David J et al. (2013) Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow Metab 33:13-21 |
| del Zoppo, Gregory J; Izawa, Yoshikane; Hawkins, Brian T (2013) Hemostasis and alterations of the central nervous system. Semin Thromb Hemost 39:856-75 |
| del Zoppo, Gregory J (2013) Plasminogen activators and ischemic stroke: conditions for acute delivery. Semin Thromb Hemost 39:406-25 |
| del Zoppo, Gregory J; Frankowski, Harald; Gu, Yu-Huan et al. (2012) Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab 32:919-32 |
| Frankowski, Harald; Gu, Yu-Huan; Heo, Ji Hoe et al. (2012) Use of gel zymography to examine matrix metalloproteinase (gelatinase) expression in brain tissue or in primary glial cultures. Methods Mol Biol 814:221-33 |
| del Zoppo, Gregory J; Sharp, Frank R; Heiss, Wolf-Dieter et al. (2011) Heterogeneity in the penumbra. J Cereb Blood Flow Metab 31:1836-51 |
| Osada, Takashi; Gu, Yu-Huan; Kanazawa, Masato et al. (2011) Interendothelial claudin-5 expression depends on cerebral endothelial cell-matrix adhesion by ?(1)-integrins. J Cereb Blood Flow Metab 31:1972-85 |
| del Zoppo, Gregory J (2010) Acute anti-inflammatory approaches to ischemic stroke. Ann N Y Acad Sci 1207:143-8 |
| del Zoppo, Gregory J (2010) Plasminogen activators in ischemic stroke: introduction. Stroke 41:S39-41 |
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