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The Journal of Neuroscience, March 26, 2008, 28(13):3324-3332; doi:10.1523/JNEUROSCI.4769-07.2008

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Neurobiology of Disease
Low Endogenous G-Protein-Coupled Receptor Kinase 2 Sensitizes the Immature Brain to Hypoxia–Ischemia-Induced Gray and White Matter Damage

Cora H. A. Nijboer,^1,2 Annemieke Kavelaars,¹ Anne Vroon,¹ Floris Groenendaal,² Frank van Bel,² and Cobi J. Heijnen¹

¹Laboratory of Psychoneuroimmunology and ²Department of Neonatology, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands

Correspondence should be addressed to Dr. Cobi J. Heijnen, University Medical Center Utrecht, Room KC 03.068.0, Lundlaan 6, 3584 EA Utrecht, The Netherlands. Email: C.Heijnen{at}umcutrecht.nl

Hypoxic–ischemic brain injury is regulated in part by neurotransmitter and chemokine signaling via G-protein-coupled receptors (GPCRs). GPCR-kinase 2 (GRK2) protects these receptors against overstimulation by inducing desensitization. Neonatal hypoxic–ischemic brain damage is preceded by a reduction in cerebral GRK2 expression. We determined the functional importance of GRK2 in hypoxic–ischemic brain damage.

Nine-day-old wild-type and GRK2^+/– mice with a 50% reduction in GRK2 protein were exposed to unilateral carotid artery occlusion and hypoxia. In GRK2^+/– animals, gray and white matter damage was aggravated at 3 weeks after hypoxia–ischemia. In addition, cerebral neutrophil infiltration was increased in GRK2^+/– animals. Neutrophil depletion reduced brain damage, but neuronal loss was still more pronounced in GRK2^+/– animals. Onset of neuronal loss was advanced in GRK2^+/– animals regardless of neutrophil depletion. White matter injury was advanced in GRK2^+/– animals and was not affected by neutrophil depletion. Activation/infiltration of microglia/macrophages was stronger in GRK2^+/– brains but only occurred 24 h after hypoxia–ischemia and is therefore not the primary cause of increased damage. During hypoxia, cerebral blood flow was reduced to the same extent in both genotypes. In vitro, GRK2^+/– hippocampal slices and cerebellar granular neurons were more sensitive to glutamate-induced death.

We propose the novel concept that the kinase GRK2 regulates onset and magnitude of hypoxic–ischemic brain damage. Increased gray and white matter damage in GRK2^+/– 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.

Key words: GPCR; GRK2; hypoxia–ischemia; knock-out mice; neonatal; neuroinflammation

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Received Oct. 22, 2007; revised Jan. 30, 2008; accepted Feb. 8, 2008.

Correspondence should be addressed to Dr. Cobi J. Heijnen, University Medical Center Utrecht, Room KC 03.068.0, Lundlaan 6, 3584 EA Utrecht, The Netherlands. Email: C.Heijnen{at}umcutrecht.nl

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