Low endogenous G-protein-coupled receptor kinase 2 sensitizes the immature brain to hypoxia-ischemia-induced gray and white matter damage.

Abstract

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.

• Authors: Cora H A Nijboer, Annemieke Kavelaars, Anne Vroon, Floris Groenendaal, Frank van Bel, Cobi J Heijnen
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 28 Issue 13 Pg. 3324-32 (Mar 26 2008) ISSN: 1529-2401 [Electronic] United States
• PMID: 18367599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• CD68 antigen, human
• Myelin Basic Protein
• Glutamic Acid
• Peroxidase
• GRK2 protein, mouse
• G-Protein-Coupled Receptor Kinase 2

Topics

• Animals
• Animals, Newborn
• Antigens, CD (metabolism)
• Antigens, Differentiation, Myelomonocytic (metabolism)
• Apoptosis
• Brain Injuries (etiology, pathology)
• G-Protein-Coupled Receptor Kinase 2 (deficiency, metabolism)
• Gene Expression Regulation, Developmental (drug effects, physiology)
• Glutamic Acid (toxicity)
• Hypoxia-Ischemia, Brain (complications)
• In Vitro Techniques
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myelin Basic Protein (metabolism)
• Neuroglia (drug effects, metabolism)
• Neurons (drug effects, metabolism)
• Neutrophil Infiltration (physiology)
• Peroxidase (metabolism)
• Regional Blood Flow (physiology)
• Subcellular Fractions (metabolism)
• Time Factors