Impact of Venlafaxine on Gene Expression Profile in Lymphocytes of the Elderly with Major Depression – Evolution of Antidepressants and the Role of the “Neuro-Immune” System
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Antidepressive drugs offer considerable symptomatic relief in mood disorders and, although commonly discovered by screening with single biological targets, most interact with multiple receptors and signaling pathways. Antidepressants require a treatment regimen of several weeks before clinical efficacy is achieved in patient populations. While the biochemical mechanisms underlying the delayed temporal profile remain unclear, molecular adaptations over time are likely involved. The selective serotonin and noradrenaline reuptake inhibitor, venlafaxine, offers a dual antidepressive action. Its pharmacological behavior, however, is unknown at the genetic level, and it is difficult to monitor in human brain samples. Because the hypothalamic-pituitary-adrenal axis is often severely disrupted in mood disorders, lymphocytes may serve as models of neuropsychiatric conditions. As such, we examined the role of venlafaxine on the gene expression profile of human lymphocytes. DNA microarray was used to measure the expression patterns of multiple genes in human lymphocytes from depressed patients treated with this mood stabilizer. In this self-controlled study, RNAs of control and treated samples were purified, converted into cDNA and labeled with either Cy3 or Cy5, mixed and hybridized to DNA microarrays containing human oligonucleotides corresponding to more than 8,000 genes. Genes that were differentially regulated in response to treatment were selected for follow up on the basis on novelty, gene identity, and level of over-expression/repression, and selected transcripts were profiled by real-time PCR (data have been normalized to β-actin). Using software analysis of the microarray data, a number of transcripts were differentially expressed between control and treated samples, of which only 57 were found to significantly vary with the “P” value of 0.05 or lower as a result of exposure to venlafaxine. Of these, 31 genes were more highly expressed and 26 transcripts were found to be significantly less abundant. Most selected genes were verified with QRT-PCR to alter. As such, independent verification using QRT-PCR demonstrated the reliability of the method. Genes implicated in ionic homeostasis were differentially expressed, as were genes associated with cell survival, neural plasticity, signal transduction, and metabolism. Understanding how gene expression is altered over a clinically relevant time course of administration of venlafaxine may provide insight into the development of antidepressant efficacy as well as the underlying pathology of mood disorders. These changes in lymphocytes are thought to occur in the brain, and a “neuro-immune system” is proposed by this study.
Key wordsAntidepressant depression gene expression lymphocyte microarray neuronal plasticity
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- 4.Ader, R., Felten, D. L., Cohen, N. 1991Psychoneuroimmunology 2Academic PressNew YorkGoogle Scholar
- 6.Blalock, J. E. 1994The immune system: our sixth senseImmunologist2815Google Scholar
- 11.Irwin, M. 1999Immune correlation of depressionAdv. Exp. Med. Biol46124Google Scholar
- 16.Zvara, Á., Szekeres, G., Janka, Z., Kelemen, J. Z., Cimmer, C., Sántha, M., Puskás, L. G. 2005Over-expression of dopamine D(2) receptor and inwardly rectifying potassium channel genes in drug-naive schizophrenic peripheral blood lymphocytes as potential diagnostic markersDis. Markers216169PubMedGoogle Scholar
- 22.Cleveland, W. S. 1974Robust locally weighted regression and smoothing scatterplotsJ. Am. Statist. Assoc74829836Google Scholar
- 23.Yang, Y. H., Dudoit, S., Luu, P., Lin, D. M., Peng, V., Ngai, J., Speed, T. P. 2002Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variationNucleic Acids Res3015Google Scholar
- 26.Yoshida, S., Yashar, B. M., Hiriyanna, S., Swaroop, A. 2002Microarray analysis of gene expression in the aging human retinaInvest. Opthalmol. Vis. Sci4325542560Google Scholar
- 28.Fehér, L. Z., Kálmán, J., Puskás, L. G., Gyülvészi, G., Kitajka, K., Penke, B., Palotás, M., Samarova, E. I., Molnár, J., Zvara, Á., Matin, K., Bódi, N., Hugyecz, M., Pákáski, M., Bjelik, A., Juhász, A., Bogáts, G., Janka, Z., and Palotás, A. 2005. Impact of haloperidol and risperidone on gene expression profile in the rat cortex. Neurochem. Int. 47:271–280Google Scholar
- 30.Rook, G. A. V. 1994Hormones, peripherally activated prohormones and regulation of immunityAnnu. Rev. Immunol20125163Google Scholar
- 31.Palotás, A., Kálmán, J., Puskás, L. G., Kemény, L., Janka, Z., and Penke, B. 2005. Calcium, and the Alzheimer’s Ca2+- tastrophe. in Coleman, R. M. (ed), Trends in Neurochemistry Research, Nova Science Publishers, IncGoogle Scholar