Stroke is a leading cause of death and disability worldwide and approximately 72% of people who suffer a stroke are over the age of 65. Tissue plasminogen activator (tPA) is the only drug approved by the Food and Drug Administration (FDA) for treatment of acute stroke (within 4.5h). The most feared complication after tPA treatment of stroke is an increased risk of cerebral hemorrhage. Our preliminary data indicate that N-acetyl- seryl-aspartyl-lysyl-proline (Ac-SDKP), a peptide normally presented in human plasma, in combination with tPA reduced infarct volume by more than 50% and improved neurological outcome, but did not increase the incidence of hemorrhagic transformation in young adult rats. In this application, we propose to develop a combination therapy of Ac-SDKP and tPA for treatment of acute stroke in aged rats and to investigate molecular mechanisms underlying the combination therapy on the neurovascular unit.
In Specific Aim 1, using MRI and 3D laser confocal microscopy, we will investigate the effect of Ac-SDKP alone and Ac-SDKP in combination with tPA on recanalization of the occluded MCA, cerebral microvascular perfusion and vascular integrity, brain hemorrhage, and ischemic neuronal damage in aged rats subjected to embolic middle cerebral artery occlusion (MCAO).
In Specific Aim 2, we will examine whether Ac-SDKP suppresses the ischemia- and tPA-activated nuclear transcription factor-?B (NF-?B) pathway in cerebral vessels, which leads to enhancement of cerebral microvascular patency and integrity by reduction of thrombosis.
In Specific Aim 3, we will examine whether Ac-SDKP blocks the ischemia- and tPA-activated transforming growth factor ? (TGF?) signaling pathway in cerebral vessels and astrocytes, which leads to reduction of thrombosis by downregulation of plasminogen activator inhibitor1 (PAI-1). These studies could potentially provide a new therapy to minimize the adverse effect of tPA on ischemic neurovascular damage, leading to improved neurological outcomes after acute stroke.

Public Health Relevance

Stroke is a leading cause of death and disability worldwide and approximately 72% of people who suffer a stroke are over the age of 65. Tissue plasminogen activator (tPA) is the only drug approved by the Food and Drug Administration (FDA) for treatment of acute stroke (within 4.5h). The most feared complication after tPA treatment of stroke is an increase risk of cerebral hemorrhage. We have found that N-acetyl-seryl-aspartyl- lysyl-proline (Ac-SDKP), a peptide normally presented in human plasma, in combination with tPA reduced infarct volume by more than 50% and improved neurological outcome, but did not increase the incidence of hemorrhagic transformation in young adult rats. In this application, we propose to develop a combination therapy of Ac-SDKP and tPA for treatment of acute stroke in aged rats and to investigate molecular mechanisms underlying the combination therapy on the neurovascular unit. Our overall hypothesis is that Ac-SDKP protects the neurovascular unit from damage induced by stroke and tPA, leading to improvement of neurological outcome. Using an embolic model of focal cerebral ischemia, we will test this hypothesis. These studies could potentially provide a new therapy to minimize the adverse effect of tPA on ischemic neurovascular damage, leading to improving neurological outcomes after acute stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS079612-01A1
Application #
8504109
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2013-05-01
Project End
2018-03-31
Budget Start
2013-05-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$324,844
Indirect Cost
$106,094
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202