Perinatal arterial stroke is one of the main causes of cerebral palsy. The immaturity of the brain in the early postnatal period increases its susceptibility to ischemic and inflammatory damage. For a long time, microglial cells were considered to be purely injurious after neonatal brain ischemia. However, work by us and others has shown that the microglial phenotypes are diverse after neonatal injury and that the balance between the cytotoxic and protective microglia may modulate injury. The scavenger receptor CD36 plays a dual role in cerebrovascular injury. CD36 can injure by triggering oxidative stress and inflammation but can protect by cleaning up neuronal debris through phagocytosis or by altering the macrophage phenotype after injury. While genetic deletion of CD36 protects the adult brain by reducing local inflammation after middle cerebral artery occlusion (MCAO), the lack of CD36 in the neonatal brain aggravates injury after acute MCAO and affects intracellular pro- inflammatory signaling differentially than in the adult. CD36-mediated effects are ligand- specific and context-dependent, and in part depend on partnering with particular Toll-like receptors (TLR). We hypothesize that CD36 ameliorates injury after neonatal stroke by altering the balance between the cytotoxic and protective microglia in a TLR2-dependent manner. We will first determine the effect of disrupted CD36 signaling (genetic deletion, pharmacological inhibition) after neonatal MCAO on the microglial phenotypes, both cytotoxic and protective and then examine the effects of CD36 inhibition on the chemotactic activity of microglia using two-photon imaging in living injured neonatal mice (Aim 1). To determine if CD36 acts through TLR2 to modify injury, we will monitor TLR2 by bioluminescence imaging in living neonatal luc/GFP-TLR2 and CD36ko-luc/GFP-TLR2 mice subjected to MCAO or, alternatively, by stimulating microglia in living neonatal mice in both a TLR2-dependent and -independent manner (Aim 2). Finally, we will determine the effects of a lack/inhibition of CD36 on Lyn-mediated intracellular signaling in cultured microglia and the effects of altered CD36/Lyn signaling on injured cultured neurons (Aim 3).
Stroke in the term newborn occurs in 1 in 4,000 live births. Most of these infants survive with significant long-term disabilities, and there are no treatments available to ameliorate their sufering and decrease the enormous cost to families and society. The mechanisms of ischemic brain injury in the neonate are stil inadequately studied, and targets for treatment have not been identified.
|Fernández-López, David; Natarajan, Niranjana; Ashwal, Stephen et al. (2014) Mechanisms of perinatal arterial ischemic stroke. J Cereb Blood Flow Metab 34:921-32|
|Fernandez-Lopez, 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|
|Dzietko, M; Derugin, N; Wendland, M F et al. (2013) Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. Transl Stroke Res 4:189-200|
|Fernandez-Lopez, 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|
|Dzietko, Mark; Wendland, Michael; Derugin, Nikita et al. (2011) Magnetic resonance imaging (MRI) as a translational tool for the study of neonatal stroke. J Child Neurol 26:1145-53|
|Biran, Valerie; Heine, Vivi M; Verney, Catherine et al. (2011) Cerebellar abnormalities following hypoxia alone compared to hypoxic-ischemic forebrain injury in the developing rat brain. Neurobiol Dis 41:138-46|
|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|
|Vexler, Zinaida S; Yenari, Midori A (2009) Does inflammation after stroke affect the developing brain differently than adult brain? Dev Neurosci 31:378-93|
|Wendland, Michael F; Faustino, Joel; West, Tim et al. (2008) Early diffusion-weighted MRI as a predictor of caspase-3 activation after hypoxic-ischemic insult in neonatal rodents. Stroke 39:1862-8|
|Denker, Sheryl P; Ji, Shaoquan; Dingman, Andra et al. (2007) Macrophages are comprised of resident brain microglia not infiltrating peripheral monocytes acutely after neonatal stroke. J Neurochem 100:893-904|
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