Low endogenous G-protein-coupled receptor kinase 2 sensitizes the immature brain to hypoxia-ischemia-induced gray and white matter damage
Low endogenous G-protein-coupled receptor kinase 2 sensitizes the immature brain to hypoxia-ischemia-induced gray and white matter damage
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DOI：
10.1523/jneurosci.4769-07.2008
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发表时间：
2008-03-26
影响因子：
5.3
通讯作者：
Heijnen, Cobi J.
中科院分区：
文献类型：
--
作者：
Nijboer, Cora H. A.;Kavelaars, Annemieke;Heijnen, Cobi J.
缺氧缺血性脑损伤部分受神经递质和趋化因子通过G蛋白偶联受体(GPCRs)信号的调节。GPCRK2(GRK2)通过诱导脱敏来保护这些受体免受过度刺激。新生儿缺氧缺血性脑损伤之前，大脑GRK2的表达减少。我们确定了GRK2在缺氧缺血性脑损伤中的功能重要性。9日龄的野生型和GRK2(+/-)小鼠的GRK2蛋白减少了50%，并暴露在单侧颈动脉阻塞和缺氧中。GRK2(+/-)动物缺氧缺血后3周灰质和白质损伤加重。此外，GRK2(+/-)动物脑中性粒细胞浸润增加。中性粒细胞减少了脑损伤，但神经元丢失在GRK2(+/-)动物中仍然更加明显。无论中性粒细胞是否耗尽，GRK2(+/-)动物的神经元丢失的发生都提前了。白质损伤在GRK2(+/-)动物中加重，不受中性粒细胞耗尽的影响。GRK2(+/-)脑内小胶质细胞/巨噬细胞的活化/浸润较强，但仅发生在缺氧缺血后24小时，因此不是损伤增加的主要原因。低氧时，两种基因型的脑血流量均有相同程度的下降。在体外，GRK2(+/-)海马片和小脑颗粒神经元对谷氨酸诱导的死亡更敏感，我们提出了新的概念，即GRK2调节缺氧缺血性脑损伤的发生和程度。GRK2(+/-)动物灰质和白质损伤的增加并不依赖于中性粒细胞的渗入，而是在检测到小胶质细胞/巨噬细胞激活之前发生的。综上所述，我们的数据表明，大脑GRK2在缺血性脑损伤中具有重要的内源性神经保护作用。
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 similar to 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 inGRK2(+/-) 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.