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, Understanding the mechanisms regulating BBB integrity in response to injury in the neonatal brain is an important first step in the identification of therapeutic targets that protect the newborn from the lifelong consequences of stroke. Blood-brain barrier disturbances contribute to injury after adult stroke. Understanding blood-brain barrier function after neonatal stroke is critical in the search for new therapies.
| van Velthoven, Cindy T; Dzietko, Mark; Wendland, Michael F et al. (2017) Mesenchymal stem cells attenuate MRI-identifiable injury, protect white matter, and improve long-term functional outcomes after neonatal focal stroke in rats. J Neurosci Res 95:1225-1236 |
| Fernández-López, David; Faustino, Joel; Klibanov, Alexander L et al. (2016) Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke. J Neurosci 36:2881-93 |
| Fernández-López, David; Natarajan, Niranjana; Ashwal, Stephen et al. (2014) Mechanisms of perinatal arterial ischemic stroke. J Cereb Blood Flow Metab 34:921-32 |
| Fernández-López, David; Faustino, Joel; Derugin, Nikita et al. (2013) Acute and chronic vascular responses to experimental focal arterial stroke in the neonate rat. Transl Stroke Res 4:179-88 |
| Woo, Moon-Sook; Wang, Xia; Faustino, Joel V et al. (2012) Genetic deletion of CD36 enhances injury after acute neonatal stroke. Ann Neurol 72:961-70 |
| Fernández-López, D; Faustino, J; Derugin, N et al. (2012) Reduced infarct size and accumulation of microglia in rats treated with WIN 55,212-2 after neonatal stroke. Neuroscience 207:307-15 |
| Fernández-López, David; Faustino, Joel; Daneman, Richard et al. (2012) Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat. J Neurosci 32:9588-600 |
| Faustino, Joel V; Wang, Xia; Johnson, Cali E et al. (2011) Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. J Neurosci 31:12992-3001 |
