Defective neuropeptide processing and ischemic brain injury: a study on proprotein convertase 2 and its substrate neuropeptide in ischemic brains.
Defective neuropeptide processing and ischemic brain injury: a study on proprotein convertase 2 and its substrate neuropeptide in ischemic brains.
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DOI：
10.1038/jcbfm.2008.161
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发表时间：
2009-04
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采用大鼠局灶性脑缺血模型，检测脑缺血诱导的皮质蛋白原转化酶2（PC 2）mRNA和蛋白表达水平及活性的变化。原位杂交分析显示，在早期再灌注小时，PC 2蛋白的水平也很高，通过免疫细胞化学和蛋白质印迹法测定的PC 2的mRNA水平的瞬时上调。当使用合成底物分析PC 2的酶活性时，在再灌注早期观察到PC 2蛋白水平仍然很高的显著降低。在这些再灌注小时，强啡肽-A（1-8）（DYN-A（1-8））（一种PC 2底物）的组织水平也降低，如通过放射免疫测定所测定的。在培养的神经元细胞中通过代谢标记对PC 2蛋白生物合成的进一步检查表明，在缺血细胞中，PC 2的蛋白水解加工大大减弱。最后，在小鼠中，脑室内施用合成DYN-A（1-8）显著降低了缺血性脑损伤的程度。在缺乏活性PC 2的小鼠中，在其他非致死性局灶性缺血后观察到加重的脑损伤。我们的结论是，脑缺血减弱PC 2和PC 2介导的神经肽加工。这种衰减可能在缺血性脑损伤的病理学中起作用。
Using a focal cerebral ischemia model in rats, brain ischemia-induced changes in expression levels of mRNA and protein, and activities of proprotein convertase 2 (PC2) in the cortex were examined. In situ hybridization analyses revealed a transient upregulation of the mRNA level for PC2 at an early reperfusion hour, at which the level of PC2 protein was also high as determined by immunocytochemistry and western blotting. When enzymatic activities of PC2 were analyzed using a synthetic substrate, a significant decrease was observed at early reperfusion hours at which levels of PC2 protein were still high. Also decreased at these reperfusion hours were tissue levels of dynorphin-A(1–8) (DYN-A(1–8)), a PC2 substrate, as determined by radioimmunoassay. Further examination of PC2 protein biosynthesis by metabolic labeling in cultured neuronal cells showed that in ischemic cells, the proteolytic processing of PC2 was greatly attenuated. Finally, in mice, an intracerebroventricular administration of synthetic DYN-A(1–8) significantly reduced the extent of ischemic brain injury. In mice those lack an active PC2, exacerbated brain injury was observed after an otherwise non-lethal focal ischemia. We conclude that brain ischemia attenuates PC2 and PC2-mediated neuropeptide processing. This attenuation may play a role in the pathology of ischemic brain injury.
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