PGE2, via EP3 receptors, regulates brain nitric oxide synthase in the perinatal period
PGE2, via EP3 receptors, regulates brain nitric oxide synthase in the perinatal period
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DOI：
10.1152/ajpregu.1998.275.6.r1812
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发表时间：
1998-12-01
影响因子：
2.8
通讯作者：
Chemtob, S
中科院分区：
文献类型：
--
作者：
Dumont, I;Peri, KG;Chemtob, S
我们测试了围产期高前列腺素水平可能调节大脑一氧化氮合酶(NNOS)表达的假设。新生大鼠和猪脑皮质和脑室周围nNOS和环氧合酶(COX)-2mRNAs的表达仅高于成年大鼠。新生儿的一氧化氮合酶活性也是成人大脑的2.5到4倍。给新生大鼠和猪每隔8小时给予非选择性COX抑制剂布洛芬或COX-2抑制剂尼美舒利，可降低前列腺素水平，并引起与成年大鼠相当的nNOS mRNA、蛋白和活性的下降；COX抑制剂引起的变化可被PGE(2)类似物16，16-二甲基-PGE(2)和PGE(2)的EP3受体激动剂舒前列酮共同处理而阻止，但不能被PGI(2)类似物Carbaprost环素、PGD(2)、EP1受体激动剂17-苯基三或-PGE(2)和EP2激动剂Butaprost所阻止。结果显示，COX抑制剂可使皮层深层神经元nNOS表达减少，EP3激动剂可阻断这种作用。总之，新生儿脑中高水平的PGE(2)通过作用于EP3受体而导致nNOS表达增加；PGE(2)与nNOS之间的这种正向相互作用可能是正常脑发育所必需的生理条件。
We tested the hypothesis that high prostaglandin levels during the perinatal period might regulate brain nitric oxide synthase (nNOS) expression. nNOS and cyclooxygenase (COX)-2 mRNAs mere higher in brain cortex and the periventricular area of newborn rats and pigs compared with adult brain. Nitric oxide synthase activity was also 2.5- to 4-fold higher in newborn than in adult brain. Administration of nonselective COX inhibitor ibuprofen or COX-2 inhibitor nimesulide every 8 h for 24 h to newborn rats and pigs reduced prostaglandin levels and caused comparable reductions in nNOS mRNA, protein, and activity to levels of adults; COX inhibitor-induced changes were prevented by cotreatment with PGE(2) analog, 16,16-dimethyl-PGE(2), and agonist for the EP3 receptor of PGE(2), sulprostone, but not by PGI(2) analog carbaprostacyclin, PGD(2), EP1 receptor agonist 17-phenyl trinor-PGE(2), and EP2 agonist butaprost. Concordant observations were made in vitro and revealed that nNOS expression (detected by NADPH diaphorase reactivity) mostly present in neurons of the deeper cortical layers was reduced by COX inhibitor, and this effect was prevented by EP3 agonist. In conclusion, high levels of PGE(2) in neonatal brain contribute to the increased expression of nNOS by acting on EP3 receptors; this positive interaction between PGE(2) and nNOS might be required physiologically for normal brain development.