It is increasingly recognized that the immaturity of the CNS at birth affects ischemic injury and recovery;thus there is an obvious need to develop age-appropriate strategies for intervention. The mature blood-brain barrier (BBB) allows precise control of substances that enter or leave the brain. In many brain diseases, including stroke, BBB breakdown is an important contributing factor to injury. Emerging data show that the BBB is developed by birth and functions effectively under normal conditions, bul il is unclear how it is affected by brain injury early in life. Our recent data in neonatal rats show that BBB permeability to proteins is preserved following transient cerebral ischemia, and neutrophil transmigration is halted despite the presence of marked transient accumulation of the cytokine-induced neutrophil chemoaUractant protein 1 (CINC-1). This is in stark contrast to the adult brain where disruption of the BBB occurs early and is mediated by chemokine?driven neutrophil infiltration into ischemic-reperfused tissue. Our goal is 10 understand the mechanisms that confer resistance of the BBB following early post-ischemia in neonates and contribu te to protection by studying the role of CINC?l in neutrophlilransmigralion and barrier integrity. We therefore propose to test the hypothesis that CINC-l protects neonatal brain by preserving blood-brain barrier integrity acutely after stroke. We will determine whether circulating CINC-1 protects BBB integrity (Aim 1) and limits neutrophil activation and migration (Aim 2) acutely after neonatal stroke. Studies will be accomplished in postnatal day 7 rats subjected to focal transient middle cerebral artery (MCA) occlusion and identified as injured by diffusion-weighted MRt during occlusion. We will use several experimental approaches, including flow cylometry, immunohistochemistry, cytokine multiplex, and MRi in animals with manipulated systemic CINC?l levels, or manipulated neutrophils.
Arterial stroke in the newborn is an existing serious and frequent disorder. Most babies survive with significant disability. Blood brain barrier disruption is an important contributing factor to ischemic injury in adults and at the same time the route for many molecules to enter the brain. Several aspects of blood brain barrier permeability are relatively preserved after neonatal stroke, in part by the endogenously produced chemokine CINC-1 (cytokine-induced neutrophil chemoattractant protein-1). Understanding the mechanisms regulating blood brain barrier integrity in response to injury in the neonatal brain, studies proposed in this application, is an important first step in the identification of therapeutic targets that protect the newborn from the lifelong consequences of stroke.
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