Chao Dongman, Donnelly David F, Feng Yin, Bazzy-Asaad Alia, Xia Ying
Department of Pediatrics, Section of Respiratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Cereb Blood Flow Metab. 2007 Feb;27(2):356-68. doi: 10.1038/sj.jcbfm.9600352. Epub 2006 Jun 14.
Central neurons are extremely vulnerable to hypoxic/ischemic insult, which is a major cause of neurologic morbidity and mortality as a consequence of neuronal dysfunction and death. Our recent work has shown that delta-opioid receptor (DOR) is neuroprotective against hypoxic and excitotoxic stress, although the underlying mechanisms remain unclear. Because hypoxia/ischemia disrupts ionic homeostasis with an increase in extracellular K(+), which plays a role in neuronal death, we asked whether DOR activation preserves K(+) homeostasis during hypoxic/ischemic stress. To test this hypothesis, extracellular recordings with K(+)-sensitive microelectrodes were performed in mouse cortical slices under anoxia or oxygen-glucose deprivation (OGD). The main findings in this study are that (1) DOR activation with [D-Ala(2), D-Leu(5)]-enkephalinamide attenuated the anoxia- and OGD-induced increase in extracellular K(+) and decrease in DC potential in cortical slices; (2) DOR inhibition with naltrindole, a DOR antagonist, completely abolished the DOR-mediated prevention of increase in extracellular K(+) and decrease in DC potential; (3) inhibition of protein kinase A (PKA) with N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide dihydrochloride had no effect on the DOR protection; and (4) inhibition of protein kinase C (PKC) with chelerythrine chloride reduced the DOR protection, whereas the PKC activator (phorbol 12-myristate 13-acetate) mimicked the effect of DOR activation on K(+) homeostasis. These data suggest that activation of DOR protects the cortex against anoxia- or ODG-induced derangement of potassium homeostasis, and this protection occurs via a PKC-dependent and PKA-independent pathway. We conclude that an important aspect of DOR-mediated neuroprotection is its early action against derangement of K(+) homeostasis during anoxia or ischemia.
中枢神经元极易受到缺氧/缺血性损伤，这是导致神经功能障碍和死亡的主要原因，会引发神经疾病的发病和死亡。我们最近的研究表明，δ-阿片受体（DOR）对缺氧和兴奋性毒性应激具有神经保护作用，但其潜在机制尚不清楚。由于缺氧/缺血会破坏离子稳态，导致细胞外钾离子（K(+)）增加，而这在神经元死亡中起作用，我们探究了DOR激活是否能在缺氧/缺血应激期间维持钾离子稳态。为了验证这一假设，我们在缺氧或氧糖剥夺（OGD）条件下，使用对K(+)敏感的微电极在小鼠皮质切片上进行了细胞外记录。本研究的主要发现如下：（1）用[D-Ala(2), D-Leu(5)]-脑啡肽酰胺激活DOR可减轻缺氧和OGD诱导的皮质切片细胞外K(+)增加以及直流电位降低；（2）用DOR拮抗剂纳曲吲哚抑制DOR可完全消除DOR介导的对细胞外K(+)增加和直流电位降低的预防作用；（3）用N-(2-[对溴肉桂基氨基]-乙基)-5-异喹啉磺酰胺二盐酸盐抑制蛋白激酶A（PKA）对DOR的保护作用无影响；（4）用白屈菜红碱抑制蛋白激酶C（PKC）会降低DOR的保护作用，而PKC激活剂（佛波醇12-肉豆蔻酸酯13-乙酸酯）模拟了DOR激活对钾离子稳态的影响。这些数据表明，DOR的激活可保护皮质免受缺氧或ODG诱导的钾离子稳态紊乱，且这种保护是通过PKC依赖性和PKA非依赖性途径实现的。我们得出结论，DOR介导的神经保护的一个重要方面是其在缺氧或缺血期间对钾离子稳态紊乱的早期作用。
