There is a compelling need to develop therapies complementary to thrombolysis for the treatment of acute stroke. In this Project, we test the hypothesis that microvascular thrombosis ensues after stroke and that platelet aggregation contributes to progression of the fulminating ischemic lesion. Thus, treatment of embolic stroke with an antagonist to the GPIIb/IIIa receptor, which binds the platelet to fibrinogen and is the terminus of platelet with an antagonist to the GPIIb/IIIa receptor, which binds the platelet to fibrinogen and is the terminus of platelet thrombosis, may enhance cerebral perfusion, reduce thrombosis and complement and enhance thrombolytic therapy of stroke with rtPA. To achieve our goals, we propose four Specific Aims:
Specific Aim 1 : Rats will be subjected to embolic stroke and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 2 : Rats will be subjected to embolic stroke and will be treated with rtPA at specific time paints after stroke (2h, 4h, 6h). The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 3 : Rats will be subjected to embolic stroke and will be treated with GP IIb/IIIa receptor antagonist at specific time points before and after stroke. The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 2 : Rats will be subjected to embolic stroke and will be treated with rtPA and specific time points after stroke (2h, 4h, 6h). The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 3 : Rats will be subjected to embolic stroke and will be treated with a GP IIb/IIIa receptor antagonist at specific time points before and after stroke. The volume of cerebral infarction and the spatiotemporal profiles of tissue perfusion and thrombosis will be measured.
Specific Aim 4 : Rats will be subjected to embolic stroke and will be treated with a combination of GPIIb/IIIa receptor antagonist and fibrinolysis with rtPA at specific time points after stroke. To test our hypotheses, we employ a clinically relevant model of embolic stroke in the rat and state-of-the-art technology, including quantita6tive scanning confocal microscopy and MRI. Our long term objective of developing anti-platelet aggregation therapy in the human is initiated in the Phase II Clinical Trial to be carried out in Project 3. This Project provides the experimental basis for reducing platelet mediated thrombosis secondary to stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
3P01NS023393-14A1S1
Application #
6573861
Study Section
Special Emphasis Panel (ZNS1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
14
Fiscal Year
2002
Total Cost
$173,158
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Knight, R A; Nagaraja, T N; Li, L et al. (2016) A Prospective Safety Trial of Atorvastatin Treatment to Assess Rebleeding after Spontaneous Intracerebral Hemorrhage: A Serial MRI Investigation. Austin J Cerebrovasc Dis Stroke 3:
Ding, Guang-Liang; Chopp, Michael; Li, Lian et al. (2014) Magnetic Resonance Imaging of Stroke in the Rat. Bo Pu Xue Za Zhi 31:116-132
Pindolia, Kirit; Li, Hong; Cardwell, Cisley et al. (2014) Characterization and functional analysis of cellular immunity in mice with biotinidase deficiency. Mol Genet Metab 112:49-56
Cui, Xu; Chopp, Michael; Zacharek, Alex et al. (2013) The neurorestorative benefit of GW3965 treatment of stroke in mice. Stroke 44:153-61
Zhang, Rui Lan; Zhang, Zheng Gang; Chopp, Michael (2013) Targeting nitric oxide in the subacute restorative treatment of ischemic stroke. Expert Opin Investig Drugs 22:843-51
Yan, Tao; Chopp, Michael; Ning, Ruizhuo et al. (2013) Intracranial aneurysm formation in type-one diabetes rats. PLoS One 8:e67949
Hernández-Vázquez, A; Wolf, B; Pindolia, K et al. (2013) Biotinidase knockout mice show cellular energy deficit and altered carbon metabolism gene expression similar to that of nutritional biotin deprivation: clues for the pathogenesis in the human inherited disorder. Mol Genet Metab 110:248-54
Xiong, Ye; Mahmood, Asim; Chopp, Michael (2013) Animal models of traumatic brain injury. Nat Rev Neurosci 14:128-42
Wang, Shiyang; Chopp, Michael; Nazem-Zadeh, Mohammad-Reza et al. (2013) Comparison of neurite density measured by MRI and histology after TBI. PLoS One 8:e63511
Santra, Manoranjan; Chopp, Michael; Zhang, Zheng Gang et al. (2012) Thymosin ? 4 mediates oligodendrocyte differentiation by upregulating p38 MAPK. Glia 60:1826-38

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