Aubry Jean-Michel, Schwald Michèle, Ballmann Eladia, Karege Félicien
Department of Psychiatry, Bipolar Program, Geneva University Hospitals and University of Geneva, 6-8 rue du 31 Décembre, CH-1207 Geneva, Switzerland.
Psychopharmacology (Berl). 2009 Aug;205(3):419-29. doi: 10.1007/s00213-009-1551-2. Epub 2009 May 14.
Lithium, some of the anticonvulsants, and several second-generation antipsychotic drugs are common medications widely prescribed to treat bipolar disorder. Molecular targets and cellular events that mediate their effects have been described for these drugs but are only partially unraveled. Few comparative studies have been performed.
We evaluated seven mood stabilizers (MS) in the same in vitro system and found several differences and similarities in their cellular mechanisms (proliferation and cell survival). As some MS were previously shown to activate the Akt/GSK-3beta axis, this pathway was explored for other drugs.
The SH-SY5Y cells were cultured in RPMI-1640 medium. Effects of MS drugs on serum-induced cell proliferation and on slowing of cell death were analyzed. Phosphorylation and expression of Akt-1 and GSK-3beta mRNA and protein were assessed for the seven drugs as well.
Lithium, Valproate, Olanzapine, and Clozapine enhance proliferation and protect cells against serum withdrawal-induced injury. These drugs also activate Akt-1 and GSK-3beta phosphorylation. Interestingly, gene expression of Akt-1 mRNA and protein, but not GSK-3beta, was increased. The other drugs Lamotrigine, Haloperidol, and Carbamazepine did not affect cellular events nor activate Akt/GSK-3beta axis.
Valproate and atypical antipsychotics (Olanzapine and Clozapine) regulate SH-SY5Y cell proliferation and survival, activate the Akt/GSK-3beta axis, and stimulate gene expression of Akt-1 mRNA and protein, as does Lithium. The other medications have no effect. The study shows the importance of the Akt/GSK-3 axis in MS actions but also pinpoints a different dependence of these drugs on this signaling axis.
锂盐、一些抗惊厥药以及几种第二代抗精神病药物是广泛用于治疗双相情感障碍的常用药物。这些药物介导其作用的分子靶点和细胞事件已被描述，但仅部分得到阐明。很少有比较研究。
我们在同一体外系统中评估了七种心境稳定剂（MS），并发现它们在细胞机制（增殖和细胞存活）方面存在一些差异和相似之处。由于先前已证明一些MS可激活Akt/GSK-3β轴，因此对其他药物探索了该途径。
SH-SY5Y细胞在RPMI-1640培养基中培养。分析了MS药物对血清诱导的细胞增殖和细胞死亡减缓的影响。还评估了七种药物的Akt-1和GSK-3βmRNA及蛋白的磷酸化和表达。
锂盐、丙戊酸盐、奥氮平和氯氮平可增强增殖并保护细胞免受血清撤药诱导的损伤。这些药物还可激活Akt-1和GSK-3β磷酸化。有趣的是，Akt-1 mRNA和蛋白的基因表达增加，但GSK-3β未增加。其他药物拉莫三嗪、氟哌啶醇和卡马西平不影响细胞事件，也不激活Akt/GSK-3β轴。
丙戊酸盐和非典型抗精神病药物（奥氮平和氯氮平）调节SH-SY5Y细胞的增殖和存活，激活Akt/GSK-3β轴，并刺激Akt-1 mRNA和蛋白的基因表达，锂盐也是如此。其他药物则无作用。该研究表明Akt/GSK-3轴在MS作用中的重要性，但也指出了这些药物对该信号轴的不同依赖性。
