Weerasinghe Gayani R, Rapoport Stanley I, Bosetti Francesca
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Brain Res Bull. 2004 Jul 15;63(6):485-9. doi: 10.1016/j.brainresbull.2004.04.005.
The mood-stabilizer lithium, when chronically administered to rats at therapeutic concentrations, has been shown to downregulate brain arachidonic acid (AA) turnover and total phospholipase A2 (PLA2) activity, as well as protein and mRNA levels of cytosolic cPLA2. These effects are accompanied by a decrease in cyclooxygenase (COX)-2 protein level, COX activity, and brain prostaglandin E2 (PGE2) concentration. The involvement of Ca2+-dependent secretory PLA2 (sPLA2) in the mechanism of action of lithium has not been investigated. The purpose of this study was to examine, whether the effect of lithium is selectively directed to cPLA2 or it also affects sPLA2 protein and enzyme activity and whether other AA metabolizing enzymes (5-lipoxygenase and cytochrome P450 epoxygenase) were also altered. Furthermore, to determine if the reduction of brain PGE2 concentration was due only to downregulation of COX-2 protein or if it also involves the terminal PGE synthase, we determined brain microsomal PGE synthase protein level. Male Fischer-344 rats were fed lithium chloride for 6 weeks, whereas, control rats were fed lithium-free chow under parallel conditions. We found that chronic lithium did not significantly change sPLA2 activity or protein level. 5-Lipoxygenase and cytochrome P450 epoxygenase protein levels were unchanged, as were levels of the terminal PGE synthase. These results indicate that the effect of lithium selectively involves the cPLA2/COX-2 pathway, which might be responsible for the therapeutic effect in bipolar disorder.
情绪稳定剂锂，当以治疗浓度长期给予大鼠时，已被证明可下调脑花生四烯酸（AA）周转率、总磷脂酶A2（PLA2）活性以及胞质型cPLA2的蛋白质和mRNA水平。这些作用伴随着环氧合酶（COX）-2蛋白质水平、COX活性和脑前列腺素E2（PGE2）浓度的降低。钙依赖性分泌型PLA2（sPLA2）在锂作用机制中的参与尚未得到研究。本研究的目的是检查锂的作用是否选择性地针对cPLA2，或者它是否也影响sPLA2蛋白质和酶活性，以及其他AA代谢酶（5-脂氧合酶和细胞色素P450环氧合酶）是否也发生改变。此外，为了确定脑PGE2浓度的降低是否仅由于COX-2蛋白质的下调，或者它是否也涉及末端PGE合酶，我们测定了脑微粒体PGE合酶蛋白质水平。雄性Fischer-344大鼠喂食氯化锂6周，而对照大鼠在平行条件下喂食无锂食物。我们发现慢性锂处理并未显著改变sPLA2活性或蛋白质水平。5-脂氧合酶和细胞色素P450环氧合酶蛋白质水平未改变，末端PGE合酶水平也未改变。这些结果表明锂的作用选择性地涉及cPLA2/COX-2途径，这可能是双相情感障碍治疗效果的原因。
