Ischemic brain injury evokes an endogenous brain parenchymal cell damage as well as an exogenous inflammatory response, which includes infiltration and accumulation of polymorphonuclear leukocytes and monocytes/macrophages, and microvascular proliferation. The migration and accumulation of neutrophils into the ischemic tissue after reperfusion is not only associated with tissue repair processes, but also may result in injury to potentially viable tissue. We propose to reduce ischemic cell damage after middle cerebral artery (MCA) occlusion in the rat by selectively blocking the intercellular adhesion molecule 1 (ICAM-1), a glycoprotein expressed on endothelial cells that facilitates leukocyte adhesion.
Three specific aims and hypotheses will be tested.
Aim 1 : The effect of administration of a monoclonal antibody to the rat ICAM-1 on reducing ischemic cell damage will be investigated in rats subjected to transient (2 hours) and permanent MCA occlusion. Ischemic cell damage will be measured as a function of dose and time of antibody administration. Hypothesis: A monoclonal antibody reactive with the ICAM-1 glycoprotein reduces ischemic cell damage after transient MCA occlusion.
Aim 2 : We will measure the temporal profiles of expression of ICAM-1 and ICAM-1 mRNA in brain after transient MCA occlusion. Hypothesis: MCA occlusion results in an increase of both ICAM-1 message and protein in ischemic brain.
Aim 3 : Mechanisms by which the anti-ICAM-1 reactive antibody reduces ischemic cell damage will be investigated. 3(a): We will measure and correlate the temporal profile of the extent of neutrophil infiltration into the ischemic tissue with ischemic cell damage. Hypothesis: Anti-ICAM-1 antibody causes a reduction of neutrophils in the ischemic tissue. Infiltration of neutrophils into the ischemic tissue precedes or is concomitant with ischemic cell damage, and contributes to ischemic cell damage after transient focal cerebral ischemia. We will perform quantitative autoradiographic measurements of local cerebral blood flow at time points after transient MCA occlusion. Hypothesis: Neutrophils may contribute to ischemic cell damage in reperfusion injury by reducing local cerebral blood flow (CBF) and extending the duration of ischemia. Our long term objective is to develop a therapeutic intervention (anti- ICAM-1 antibody) to be employed after the onset of ischemic stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033627-04
Application #
2655495
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Jacobs, Tom P
Project Start
1995-02-01
Project End
1999-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Henry Ford Health System
Department
Neurology
Type
Schools of Medicine
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Zhang, Zheng Gang; Jiang, Quan; Zhang, Ruilan et al. (2003) Magnetic resonance imaging and neurosphere therapy of stroke in rat. Ann Neurol 53:259-63
Lu, Mei; Chen, Jieli; Lu, Dunyue et al. (2003) Global test statistics for treatment effect of stroke and traumatic brain injury in rats with administration of bone marrow stromal cells. J Neurosci Methods 128:183-90
Zhang, Li; Zhang, Zheng Gang; Zhang, Rui Lan et al. (2003) Effects of a selective CD11b/CD18 antagonist and recombinant human tissue plasminogen activator treatment alone and in combination in a rat embolic model of stroke. Stroke 34:1790-5
Zhang, Ruilan; Wang, Ying; Zhang, Li et al. (2002) Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33:2675-80
Zhang, Zheng Gang; Zhang, Li; Tsang, Wayne et al. (2002) Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab 22:379-92
Zhang, Zhenggang; Zhang, Li; Yepes, Manuel et al. (2002) Adjuvant treatment with neuroserpin increases the therapeutic window for tissue-type plasminogen activator administration in a rat model of embolic stroke. Circulation 106:740-5
Zhang, Zheng Gang; Zhang, Li; Jiang, Quan et al. (2002) Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 90:284-8
Zhang, Z G; Zhang, L; Croll, S D et al. (2002) Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience 113:683-7
Lu, D; Mahmood, A; Wang, L et al. (2001) Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome. Neuroreport 12:559-63
Zhang, Z G; Tsang, W; Zhang, L et al. (2001) Up-regulation of neuropilin-1 in neovasculature after focal cerebral ischemia in the adult rat. J Cereb Blood Flow Metab 21:541-9

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