Di Daniel Elena, Cheng Lili, Maycox Peter R, Mudge Anne W
Schizophrenia and Bipolar Neurophysiology and Pharmacology Research Department, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Third Avenue, Harlow, Essex, CM19 5AW, UK.
Mol Cell Neurosci. 2006 May-Jun;32(1-2):27-36. doi: 10.1016/j.mcn.2006.01.015. Epub 2006 Mar 13.
We previously showed that the mood stabilizers lithium, valproate (VPA), and carbamazepine (CBZ) have a common, inositol-reversible effect on the dynamic behavior of sensory neurons, suggesting that they all inhibit phosphoinositide (PIns) synthesis. We now report similar effects of the drugs in cortical neurons and show by mRNA analysis that these neurons do not express myo-inositol-1-phosphate synthase (MIP-synthase) or the sodium-dependent myo-inositol transporters (SMIT1 and SMIT2), but they do express the H+/myo-inositol transporter (HMIT) mRNA and protein. We used glycogen synthase kinase-3 (GSK3) inhibitors and Western blotting of GSK3 targets to confirm that the common effects of the drugs on both sensory and cortical neuron growth cones are inositol-dependent and GSK3-independent. Moreover, the anti-convulsant drugs gabapentin and phenytoin do not mimic the mood stabilizers. These results confirm that the common inositol-reversible effect of mood stabilizers on neurons does not involve GSK3 and further show that the effects are independent of MIP-synthase and SMIT transporters.
我们之前的研究表明，情绪稳定剂锂盐、丙戊酸盐（VPA）和卡马西平（CBZ）对感觉神经元的动态行为具有共同的、可被肌醇逆转的作用，这表明它们均抑制磷酸肌醇（PIns）的合成。我们现在报告这些药物在皮质神经元中也有类似作用，并通过mRNA分析表明，这些神经元不表达肌醇-1-磷酸合酶（MIP-合酶）或钠依赖性肌醇转运体（SMIT1和SMIT2），但它们确实表达H⁺/肌醇转运体（HMIT）的mRNA和蛋白质。我们使用糖原合酶激酶-3（GSK3）抑制剂以及对GSK3靶点进行蛋白质印迹分析，以确认药物对感觉神经元和皮质神经元生长锥的共同作用是依赖于肌醇且不依赖于GSK3的。此外，抗惊厥药物加巴喷丁和苯妥英不能模拟情绪稳定剂的作用。这些结果证实，情绪稳定剂对神经元的共同的、可被肌醇逆转的作用不涉及GSK3，并且进一步表明这些作用独立于MIP-合酶和SMIT转运体。
