Mechanisms Of Action: Lithium And Other Antimanic Drugs

(1)长期给锂可使大鼠脑磷脂中花生四烯酸的周转减少80%，但不影响二十二碳六烯酸和棕榈酸的周转。花生四烯醇辅酶a（花生四烯酸并入磷脂的前体）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 （cPLA2）的mRNA和蛋白质水平以及酶活性，该酶在受体介导的信号转导过程中从磷脂中释放花生四烯酸。cPLA2和花生四烯酸级联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。脑磷脂内花生四烯酸周转减少30%，但cPLA2蛋白不变。丙戊酸盐和锂都可能通过抑制脑内花生四烯酸酯的转换来治疗双相情感障碍，锂通过靶向cPLA2，丙戊酸通过一种未知的机制。(3) 1h磁共振波谱（MRS）显示65Dn三体小鼠（唐氏综合症21三体模型）脑肌醇浓度升高。据报道，唐氏综合症患者的脑肌醇含量也有类似的下降。慢性锂治疗进一步降低了小鼠的脑肌醇，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)建立了一种质谱分析方法，表明培养的胎鼠神经元中磷脂酰肌醇的肌醇周转速度非常快，每小时可达10.3%。该光谱法与相应的数学模型也可以定量鼠脑内肌醇周转。

(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.