Bosetti Francesca, Weerasinghe Gayani R, Rosenberger Thad A, Rapoport Stanley I
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurochem. 2003 May;85(3):690-6. doi: 10.1046/j.1471-4159.2003.01701.x.
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 B2 and prostaglandin E2 (PGE2), 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 B4 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 PGE2 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.
丙戊酸钠是一种情绪稳定剂，当长期给大鼠腹腔注射丙戊酸钠（每天200毫克/千克，持续30天）时，可显著降低大脑中环氧合酶（COX）-1和COX-2的蛋白质水平，但不会改变这些酶的mRNA水平。COX活性降低，通过COX产生的花生四烯酸（AA）代谢产物11-脱氢血栓素B2和前列腺素E2（PGE2）的大脑浓度也降低。相比之下，5-脂氧合酶的大脑蛋白质水平及其AA代谢产物白三烯B4的浓度没有变化。鉴于已发表的证据表明，长期给大鼠注射氯化锂，与慢性丙戊酸盐一样，会降低大脑磷脂内的AA周转率，并且锂在转录后下调COX-2但不影响COX-1的蛋白质水平和酶活性，这些观察结果表明，情绪稳定剂通常会调节大脑磷脂内AA的释放和再循环，以及AA通过COX-2转化为PGE2和相关类花生酸的过程。如果针对“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COX-2抑制剂可能在双相情感障碍中证明是有效的。
