Williams Robin S B, Cheng Lili, Mudge Anne W, Harwood Adrian J
Intracellular Signalling Group, MRC Laboratory for Molecular Cell Biology, University College London, Gower St, London WC1E 6BT, UK.
Nature. 2002 May 16;417(6886):292-5. doi: 10.1038/417292a.
Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion and to inhibition of histone deacetylase (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.
锂盐、卡马西平和丙戊酸是治疗双相情感障碍有效的心境稳定剂。这些药物作用以及该疾病本身潜在的分子机制尚不清楚。贝里奇及其同事提出，肌醇耗竭可能是锂盐治疗双相情感障碍的作用方式，但也有人认为糖原合酶激酶（GSK3）可能是相关靶点。丙戊酸的作用与肌醇耗竭以及组蛋白脱乙酰酶（HDAC）的抑制均有关联。我们在此表明，这三种药物均可抑制感觉神经元生长锥的塌陷并增加生长锥面积。这些效应并不依赖于GSK3或HDAC的抑制。然而，肌醇可逆转药物对生长锥的作用，因此表明肌醇耗竭参与了它们的作用。此外，盘基网柄菌的发育对锂盐和丙戊酸敏感，但通过缺失编码脯氨酰寡肽酶的基因可使其对二者均产生抗性，脯氨酰寡肽酶也调节肌醇代谢。脯氨酰寡肽酶抑制剂可逆转这三种药物对感觉神经元生长锥面积和塌陷的作用。这些结果提示了双相情感障碍及其治疗的分子基础。
