PT  - JOURNAL ARTICLE
AU  - Cora H. A. Nijboer
AU  - Annemieke Kavelaars
AU  - Anne Vroon
AU  - Floris Groenendaal
AU  - Frank van Bel
AU  - Cobi J. Heijnen
TI  - Low Endogenous G-Protein-Coupled Receptor Kinase 2 Sensitizes the Immature Brain to Hypoxia–Ischemia-Induced Gray and White Matter Damage
AID  - 10.1523/JNEUROSCI.4769-07.2008
DP  - 2008 Mar 26
TA  - The Journal of Neuroscience
PG  - 3324--3332
VI  - 28
IP  - 13
4099  - http://www.jneurosci.org/content/28/13/3324.short
4100  - http://www.jneurosci.org/content/28/13/3324.full
SO  - J. Neurosci.2008 Mar 26; 28
AB  - 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.