Antimanic therapies target brain arachidonic acid signaling: Lessons learned about the regulation of brain fatty acid metabolism
Antimanic therapies target brain arachidonic acid signaling: Lessons learned about the regulation of brain fatty acid metabolism
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DOI：
10.1016/j.plefa.2007.10.018
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发表时间：
2007-11-01
影响因子：
3
通讯作者：
Bazinet, Richard P.
中科院分区：
文献类型：
--
作者：
Lae, Ho-Joo;Rao, Jagadeesh S.;Bazinet, Richard P.
双相情感障碍是世界范围内的主要医疗、社会和经济负担。然而，这种疾病的生化基础和有效的抗双相情感障碍药物的作用机制仍然难以捉摸。在本文中，我们回顾了如何结合动力学方法来研究非麻醉大鼠脑磷脂内脂肪酸的周转率，沿着长期给予治疗相关剂量的抗躁狂药物（锂，丙戊酸盐和卡马西平），表明脑花生四烯酸级联反应是这些药物的共同靶点。这三种药物的重叠作用是降低花生四烯酸的周转率，但不降低大鼠脑磷脂中的二十二碳六烯酸的周转率，并降低脑环氧合酶-2和前列腺素E-2。锂和卡马西平靶向花生四烯酸选择性钙依赖性胞浆磷脂酶A的转录（2），而丙戊酸盐是花生四烯酸选择性酰基辅酶A合成酶的非竞争性抑制剂。两种潜在的双相情感障碍模型，慢性N-甲基-D-天冬氨酸和n-3多不饱和脂肪酸剥夺，与抗躁狂药物相反，增加了大鼠大脑中花生四烯酸级联的营业额和标志物。这些观察结果支持Rapoport及其同事提出的假设，即花生四烯酸级联是情绪稳定剂的常见靶标，并且通过靶向底物特异性酶，可以在大脑内调节单个脂肪酸的周转。爱思唯尔有限公司出版
Bipolar disorder is a major medical, social and economic burden worldwide. However, the biochemical basis of the disorder and the mechanisms of action of effective antibipolar disorder drugs remain elusive. In this paper, we review how combining a kinetic approach to studying the turnover of fatty acids within brain phospholipids of unanesthetized rats along with chronic administration of antimanic drugs (lithium, valproate and carbamazepine) at therapeutically relevant doses, shows that the brain arachidonic acid cascade is a common target of these drugs. The overlapping effects of the three drugs are decreased turnover of arachidonic acid but not of docosahexaenoic acid in rat brain phospholipids, and decreased brain cyclooxygenase-2 and prostaglandin E-2. Whereas lithium and carbamazepine target the transcription of the arachidonic acid-selective calcium-dependent cytosolic phospholipase A(2), valproate is a non-competitive inhibitor of an arachidonic acid-selective acyl-CoA synthetase. Two potential models of bipolar disorder, chronic N-methyl-D-aspartate and n-3 polyunsaturated fatty acid deprivation, opposite to the antimanic drugs, increase the turnover and markers of the arachidonic acid cascade in rat brain. These observations support the hypothesis proposed by Rapoport and colleagues that the arachidonic acid cascade is a common target of mood stabilizers and that by targeting substrate-specific enzymes the turnover of individual fatty acids can be regulated within the brain. Published by Elsevier Ltd.