Low endogenous G-protein-coupled receptor kinase 2 sensitizes the immature brain to hypoxia-ischemia-induced gray and white matter damage.
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 approximately 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.
Nijboer
Cora H A
CH
Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands.
Kavelaars
Annemieke
A
Vroon
Anne
A
Groenendaal
Floris
F
van Bel
Frank
F
Heijnen
Cobi J
CJ
D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000172:deficiency / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000633:toxicity; D020925:Hypoxia-Ischemia, Brain / Q000150:complications; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D054769:G-Protein-Coupled Receptor Kinase 2; D018698:Glutamic Acid; D004676:Myelin Basic Protein; D009195:Peroxidase; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C496568:GRK2 protein, mouse