Microarray gene expression profiles in neuronal and glial cell lines after lithium, valproate, carbamazepine and lamotrigine treatment
Z. YU; C. TANAKA; H. KOMATSU; S. TAKAHASHI; H. KIM; K. KIMURA; I. SORA; W. BUNNEY; H. TOMITA
Society for Neuroscience. 2008.
Lithium, valproic acid (VPA), carbamazepine, and lamotrigine- the four most often prescribed mood stabilizers have been used in the treatment of bipolar disorder patients. Common molecular targets of the multiple mood stabilizers have been sought, and multiple molecular mechanisms, including glycogen synthase kinase-3ß (GSK-3ß) molecule and inositol phosphate metabolism, have been considered candidates. For example, lithium and VPA are known to directly inhibit glycogen synthase kinase-3 (GSK-3) activity. Lithium and VPA also indirectly inhibits GSK-3 by triggering phosphorylation of GSK-3αSer21 and/or ßSer9. Furthermore, it was shown that lamotrigine protected neuronal cell lines from GSK-3ß-facilitated apoptosis. These results demonstrate that several mood disorders provide neuroprotection by inhibiting the pro-apoptotic effects of GSK-3ß. On the other hand, it has been shown that mood stabilizers regulate gene expression levels of certain candidate genes, including BCL2, and the dugs may exerts mood stabilizing effects via altering expression profiles of the brain, as downstream effects of GSK3ß suppression, inositol depletion, or some unknown alternative molecular mechanisms. On the other hand, lithium is considered to affect certain gene expressions, and also to have biological effects specific to certain types of neuronal and/or glial cells. Therefore, it is important to study the common effects of the four mood stabilizers on gene expression profiles specific to neuron, astrocyte and oligodendrocyte. In order to evaluate comprehensive gene expression profiles, we cultured neuron-derived cell line (SK-N-SH) and oligodendrocyte-derived cell line (OL) with or without lithium, VPA, carbamazepine and lamotrigine at therapeutic concentrations in the brain for 5 days. Extracted total messenger RNA samples were applied on Illumina Human-6 V2 microarray to analysis global changes in mRNA expression, compared with no treated control samples. Signal intensities for each transcript were extracted with BeadStudio 3.1 software using the average normalization. The microarray expression data was validated with quantitative RT-PCR. We picked up commonly altered genes after treatment with multiple mood stabilizers, using the criteria: fold change > 1.5 commonly after treatment with two or more mood stabilizers in at least cell line. There are 17 down-regulated genes commonly observed in both OL and SK-N-SH cells. Two genes were down-regulated only in OL cells, and another 2 genes were down-regulated only in SK-N-SH cells. These genes may be involved in the mechanism of actions of mood disorders.