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We determined the functional importance of GRK2 in hypoxic\u2013ischemic brain damage.<\/jats:p><jats:p>Nine-day-old wild-type and GRK2<jats:sup>+\/\u2212<\/jats:sup>mice with a \u223c50% reduction in GRK2 protein were exposed to unilateral carotid artery occlusion and hypoxia. In GRK2<jats:sup>+\/\u2212<\/jats:sup>animals, gray and white matter damage was aggravated at 3 weeks after hypoxia\u2013ischemia. In addition, cerebral neutrophil infiltration was increased in GRK2<jats:sup>+\/\u2212<\/jats:sup>animals. Neutrophil depletion reduced brain damage, but neuronal loss was still more pronounced in GRK2<jats:sup>+\/\u2212<\/jats:sup>animals. Onset of neuronal loss was advanced in GRK2<jats:sup>+\/\u2212<\/jats:sup>animals regardless of neutrophil depletion. White matter injury was advanced in GRK2<jats:sup>+\/\u2212<\/jats:sup>animals and was not affected by neutrophil depletion. Activation\/infiltration of microglia\/macrophages was stronger in GRK2<jats:sup>+\/\u2212<\/jats:sup>brains but only occurred 24 h after hypoxia\u2013ischemia and is therefore not the primary cause of increased damage. During hypoxia, cerebral blood flow was reduced to the same extent in both genotypes.<jats:italic>In vitro<\/jats:italic>, GRK2<jats:sup>+\/\u2212<\/jats:sup>hippocampal slices and cerebellar granular neurons were more sensitive to glutamate-induced death.<\/jats:p><jats:p>We propose the novel concept that the kinase GRK2 regulates onset and magnitude of hypoxic\u2013ischemic brain damage. Increased gray and white matter damage in GRK2<jats:sup>+\/\u2212<\/jats:sup>animals was not dependent on infiltrating neutrophils and occurred before microglia\/macrophage activation was detected. Collectively, our data suggest that cerebral GRK2 has an important endogenous neuroprotective role in ischemic cerebral damage.<\/jats:p>","DOI":"10.1523\/jneurosci.4769-07.2008","type":"journal-article","created":{"date-parts":[[2008,3,26]],"date-time":"2008-03-26T16:36:32Z","timestamp":1206549392000},"page":"3324-3332","source":"Crossref","is-referenced-by-count":30,"title":["Low Endogenous G-Protein-Coupled Receptor Kinase 2 Sensitizes the Immature Brain to Hypoxia\u2013Ischemia-Induced Gray and White Matter Damage"],"prefix":"10.1523","volume":"28","author":[{"given":"Cora H. 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