Selective increase of neuronal cyclooxygenase-2 (COX-2) expression in vulnerable brain regions of rats with experimental Wernicke's encephalopathy: effect of nimesulide
Selective increase of neuronal cyclooxygenase-2 (COX-2) expression in vulnerable brain regions of rats with experimental Wernicke's encephalopathy: effect of nimesulide
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DOI：
10.1007/s11011-008-9089-2
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发表时间：
2008-06-01
影响因子：
3.6
通讯作者：
Butterworth, Roger F.
中科院分区：
文献类型：
--
作者：
Gu, Baoying;Desjardins, Paul;Butterworth, Roger F.
硫胺素缺乏(TD)在人类和实验动物中都会导致严重的线粒体功能障碍，并导致间脑和小脑结构中选择性的神经细胞死亡。我们研究了环氧合酶-2(COX-2)在硫胺素缺乏大鼠的易损区域(内侧丘脑、下丘)和备用区域(额叶皮质)的表达。在TD的脑病症状期(14天)，COX-2mRNA的表达选择性地增加(两倍，p<；0.001)，与配对喂养的对照组或症状前(12天)的大鼠相比。伴随着COX-2表达的诱导伴随着TD症状期脆弱区域前列腺素E2(PGE_2)合成的显著增加(两到三倍，p<；0.001)。脑病症状期COX-2免疫标记显示神经元定位，COX-2免疫反应阳性神经元明显增多。尼美舒利是一种高度特异的COX-2抑制剂，它的应用显著降低了脆弱区域的PGE-2水平，但并没有起到神经保护作用，而是引发了脑病，并加剧了TD引起的神经细胞死亡。这些发现表明，新合成的前列腺素类化合物对TD具有神经保护作用。
Thiamine deficiency (TD) in both humans and experimental animals results in severe mitochondrial dysfunction and leads to selective neuronal cell death in diencephalic and cerebellar structures. We have investigated cyclooxygenase-2 (COX-2) expression in vulnerable (medial thalamus, inferior colliculus) and spared (frontal cortex) regions of rats with thiamine deficiency. Expression of COX-2 mRNA was selectively increased (twofold, p < 0.001) in vulnerable regions at symptomatic stages of encephalopathy (14 days) of TD compared to pair-fed controls or presymptomatic (days 12) rats. Induction of COX-2 expression was accompanied by a significant increase (two-to threefold, p < 0.001) in prostanglandin E2 (PGE2) synthesis in vulnerable regions at symptomatic stages of TD. COX-2 immunolabeling revealed a neuronal localization and COX-2 immunoreactive neurons were significantly increased at symptomatic stages of encephalopathy. Administration of nimesulide, a highly specific COX-2 inhibitor, significantly reduced PGE-2 levels in vulnerable regions but, rather than being neuroprotective, precipitated encephalopathy and exacerbated neuronal cell death due to TD. These findings suggest that newly synthesized prostanoids exert a neuroprotective role in TD.