Pediatric stroke is an emerging field. Research in humans suggests that pediatric stroke differs from neonatal stroke, but there are no animal models that can help identify the mechanisms of pediatric stroke. Immaturity markedly affects the neuroinflammatory mechanisms of injury, as we showed in a rodent model of neonatal focal stroke and in a similar model in the adult. Furthermore, blood-brain barrier (BBB) integrity is strikingly better preserved in acute neonatal stroke than in adult stroke. While paradoxical, this conclusion is supported by several lines of evidence, including the functional and structural integrity of the BBB and the differential gene and protein expression of an array of BBB proteins. A study showing the disrupted BBB in juvenile rats but not in newborn rats following an intracerebral inflammatory challenge suggested that the susceptibility of the BBB to injury is age- dependent;thus, the response of the BBB to neonatal and pediatric stroke may differ greatly. We hypothesize that the mechanisms of pediatric and neonatal stroke differ in part due to the distinct maturational status of the BBB. To identify the differential BBB response of neonatal and juvenile brain to stroke, we wil focus on developmentaly regulated BBB mechanisms that are "mute" in neonatal rodents but active in juvenile rodents. We wil use our wel-characterized focal stroke models in postnatal day 7 (P7) rats and P9 mice and focal stroke models in juvenile rats and mice to determine if BBB integrity is disturbed after acute pediatric arterial stroke (Aim 1), and if microglia/monocytes differentially affect BBB permeability after neonatal and pediatric stroke (Aim 2). The functional and structural integrity of the BBB will be determined in animals with and without the additional challenge of tight junction integrity after stroke. The relationship between microglial activation and BBB permeability (intravascular tracers) wil be determined by 2-photon imaging of living Cx3cr1GFP/+ neonatal and juvenile mice after stroke. The extent of the involvement of peripheral and brain macrophages in injury and in the disruption of the BBB will be determined in novel Cx3cr1GFP/+/CCR2RFP/+ knock-in mice in both age groups.

Public Health Relevance

Pediatric ischemic stroke occurs 1 in 3,000-5,000. Arterial ischemic stroke accounts for approximately 50% of strokes in children, and only 24% of children are neurologically normal after a stroke. It is important to understand the mechanisms of the disease to develop appropriate therapies and improve bench-to-bed translation in pediatric stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Developmental Brain Disorders Study Section (DBD)
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Koenig, James I
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University of California San Francisco
Schools of Medicine
San Francisco
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Fernández-López, David; Natarajan, Niranjana; Ashwal, Stephen et al. (2014) Mechanisms of perinatal arterial ischemic stroke. J Cereb Blood Flow Metab 34:921-32