Mechanisms Of Action: Lithium And Other Antimanic Drugs

作用机制：锂和其他抗躁狂药物

• 批准号: 6521733
• 负责人: Stanley I. Rapoport
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6521733
• 关键词: Downs syndrome; biological signal transduction; bipolar depression manic phase; brain metabolism; disease /disorder model; eicosanoid metabolism; laboratory mouse; lithium; mass spectrometry; mental disorder chemotherapy; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; pharmacokinetics; phospholipase A2; phospholipids; psychopharmacology; valproate

(1) Chronic lithium administration reduced arachidonic acid turnover in rat brain phospholipids by 80%, without affecting turnover of docosahexaenoic or palmitic acid. The brain concentration of arachidonoyl-CoA, the precursor for arachidonic acid incorporation into phospholipids, was reduced by 50%. Lithium also reduced mRNA and protein levels and enzyme activity of an arachidonate selective cytosolic phospholipase A2 (cPLA2), which releases arachidonic acid from phospholipids during receptor-mediated signal transduction. cPLA2 and the arachidonic acid cascade may be a target of lithium in the treatment of bipolar disorder. (2) Rats were chronically administered valproic acid, an anticonvulsant used to treat bipolar disorder. Arachidonic acid turnover within brain phospholipids was reduced by 30%, but cPLA2 protein was unchanged. Both valproate and lithium may act against bipolar disorder by inhibiting brain arachidonate turnover, lithium by targeting cPLA2, valproate by an as yet unknown mechanism. (3) 1H-magnetic resonance spectroscopy (MRS) showed an elevated brain myoinositol concentration in the trisomy 65Dn mouse, a model for Down syndrome (trisomy 21). A similar reduction in brain myoinositol was reported in Down syndrome. Chronic lithium treatment further reduced brain myoinositol in the mouse, consistent with a hypothesis that lithium inhibits brain inositol monophosphatase and the phosphatidylinositol cycle. (4) A mass spectrometry method was developed and used to show that turnover of myoinositol in phosphatidylinositol of cultured fetal mouse neurons was quite rapid, 10.3% per hour. The spectrometric method with an accompanying mathematical model can also quantify myoinositol turnover in the rodent brain in vivo.

(1)长期锂管理减少花生四烯酸营业额在大鼠脑磷脂80%，而不影响营业额的二十二碳六烯酸或棕榈酸。花生四烯酸结合到磷脂中的前体花生四烯酸-CoA的脑浓度降低了50%。锂还降低了花生四烯酸选择性胞质磷脂酶A2（cPLA 2）的mRNA和蛋白质水平以及酶活性，cPLA 2在受体介导的信号转导过程中从磷脂中释放花生四烯酸。cPLA 2和花生四烯酸级联反应可能是锂治疗双相情感障碍的靶点。(2)大鼠长期服用丙戊酸，一种用于治疗双相情感障碍的抗惊厥药。脑磷脂中花生四烯酸的周转率降低了30%，但cPLA 2蛋白没有变化。丙戊酸盐和锂剂均可通过抑制脑花生四烯酸转换来治疗双相情感障碍，锂剂通过靶向cPLA 2，丙戊酸盐通过一种未知的机制。(3)1H-磁共振波谱（MRS）显示，在65 Dn三体小鼠（唐氏综合征（21三体）模型）中，脑肌醇浓度升高。唐氏综合症患者的脑肌醇也有类似的减少。长期锂治疗进一步减少了小鼠的脑肌醇，这与锂抑制脑肌醇单磷酸酶和磷脂酰肌醇循环的假设一致。(4)一个质谱方法的开发和使用显示，周转肌醇磷脂酰肌醇的培养胎鼠神经元是相当迅速的，每小时10.3%。光谱方法与伴随的数学模型也可以量化肌醇营业额在啮齿动物大脑在体内。