Valproic acid down-regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase-1 and-2 in rat brain
Valproic acid down-regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase-1 and-2 in rat brain
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DOI：
10.1046/j.1471-4159.2003.01701.x
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发表时间：
2003-05-01
影响因子：
4.7
通讯作者：
Rapoport, SI
中科院分区：
文献类型：
--
作者：
Bosetti, F;Weerasinghe, GR;Rapoport, SI
大鼠长期给予丙戊酸钠（一种情绪稳定剂）（200 mg/kg，每日i. p.，持续30天）可显著降低环氧合酶（考克斯）-1和考克斯-2的脑蛋白水平，而不改变这些酶的mRNA水平。考克斯活性降低，脑内11-脱氢血栓烷B-2和前列腺素E-2（PGE（2））的浓度也降低，这两种物质是通过考克斯产生的花生四烯酸（AA）的代谢物。与此相反，5-脂氧合酶的脑蛋白水平及其AA代谢物白三烯B-4的浓度不变。鉴于已发表的证据表明，大鼠长期给予氯化锂（如长期丙戊酸盐）可降低脑磷脂中AA的周转，锂可转录后下调考克斯-2但不下调考克斯-1蛋白水平和酶活性，这些观察结果表明，情绪稳定剂通常可调节脑磷脂中AA的释放和再循环，以及AA通过考克斯-2转化为PGE（2）和相关的类二十烷酸。如果靶向“AA级联反应”的这一部分解释了它们的治疗作用，那么非甾体抗炎药或选择性考克斯-2抑制剂可能证明对双相情感障碍有效。
Sodium valproate, a mood stabilizer, when chronically administered to rats (200 mg/kg i.p. daily for 30 days) significantly reduced the brain protein levels of cyclooxygenase (COX)-1 and COX-2, without altering the mRNA levels of these enzymes. COX activity was decreased, as were the brain concentrations of 11-dehydrothromboxane B-2 and prostaglandin E-2 (PGE(2)), metabolites of arachidonic acid (AA) produced via COX. In contrast, the brain protein level of 5-lipoxygenase and the concentration of its AA metabolite leukotriene B-4 were unchanged. In view of published evidence that lithium chloride administered chronically to rats, like chronic valproate, reduces AA turnover within brain phospholipids, and that lithium post-transcriptionally down-regulates COX-2 but not COX-1 protein level and enzyme activity, these observations suggest that mood stabilizers generally modulate the release and recycling of AA within brain phospholipids, and the conversion of AA via COX-2 to PGE(2) and related eicosanoids. If targeting this part of the 'AA cascade' accounts for their therapeutic action, non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors might prove effective in bipolar disorder.