Detailed contribution information
| Contribution title | 3355 - The Wnt pathway hypothesis: New transitions of neuronal culture models investigating Methylphenidate mechanism |
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| Contribution code | PS03-49 (P) |
| Authors | |
| Form of presentation | Poster |
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| Abstract |
The psychostimulant Methylphenidate (MPH) is the most commonly prescribed drug treatment in attention-deficit hyperactivity disorder (ADHD). Several studies could demonstrate brain development and maturation delay in ADHD, while MPH treatment showed no cortical thinning as in non-treated ADHD 1. Previously, we demonstrated, in a pilot study looking into neuronal maturation effects in murine neural stem cells, that MPH (dose 0-100nM in the range of 1mg/kg MPH known to result in 20-40nM MPH in patients serum 2,3) enhanced cell differentiation/maturation while inhibited cell proliferation (known as risk of cancer 4), which we could further confirm and expand looking at doses up to 100µM. Testing this effect further, using two additional cell culture models: rat PC12 cells and the human SH-SY5Y cells, both dopaminergic cell lines, we could repeatedly confirm abortion of cell proliferation by MPH treatment (BrdU and the real-time impedance cell monitoring-xCELLigence). Furthermore, in both cell lines neuronal differentiation/maturation could be observed following MPH treatment (neurite-outgrowth kit). Following, we hypothesized the possible involvement of the Wnt signaling in MPH treatment. To prove this, SH-SY5Y cells were treated with either R-spo1 (Wnt activator), GBR-12909 (selective dopamine transporter inhibitor), or 30 minutes before MPH treatment with DKK1 (LRP inhibitor- inhibiting Wnt signaling). Proliferation was inhibited by R-spo1 but not GBR-12909 or DKK1+MPH. Differentiation was significantly enhanced by R-spo1 as MPH, while GBR-12909 and DKK1+MPH even caused a reduction in differentiation. These new results may open a new venue to MPH mechanism of action and explain long term MPH effects via Wnt signaling alterations. 1 Shaw, P. et al. Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder. Am J Psychiatry 166, 58-63, (2009). 2 Gualtieri, C. T. et al. Clinical studies of methylphenidate serum levels in children and adults. J Am Acad Child Psychiatry 21, 19-26 (1982). 3 Studer, S. et al. Methylphenidate and ritalinic acid determination in serum and saliva from patients with attention deficit hyperactivity disorder, <http://chromsystems.com/en-gb/news/posters-and-publications/2014_MPHPoster.pdf> (2014). 4 Bartl, J., Mori, T., Riederer, P., Ozawa, H. & Grünblatt, E. Methylphenidate enhances neural stem cell differentiation. J Mol Psychiatry 1, 5, (2013). |