Methylphenidate: Investigations of its molecular mechanism of action

Contact person

Prof. Dr. Edna Grünblatt

Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital
University of Zürich

edna.gruenblatt@kjpd.uzh.ch

Duration

Since 01.05.2012 - on going

Project

Methylphenidate: Investigations of its molecular mechanism of action in ADHD patient-specific neural cell lines

The pharmacological treatment in patient suffering from Attention-Deficit/Hyperactivity Disorder (ADHD) with the stimulant methylphenidate (MPH) often known as Ritalin® (racemic MPH), is one of the most controversy discussed issue in the last few years between public, politicians, teachers, parents, school officials and researcher. One of the main reasons for these emotional discussions is the gap of knowledge concerning the detailed mechanism of action and the influence of MPH on brain development/maturation and its long-term effect on brain structure and function. According to genetic studies, one of the main pathways involved in ADHD is the Wnt signaling pathway, which orchestrates important cellular process such as proliferation and differentiation. We hypothesize that altered Wnt might underlie the brain maturational delays seen clinically in ADHD patients and that MPH is able to restore its activity, based on previous findings from our group. Therefore, our lab has set an overall objective to achieve at the first step more clarity regarding the molecular mechanism of action of MPH in cells derived from ADHD patients. This can be accomplished by the use of human induced pluripotent stem cells (iPSCs), generated from Peripheral Mononuclear Blood Cells (PBMCs) or keratinocytes collected from ADHD patients responding or not to MPH treatment. By using the iPSC technology, we will differentiate Neural Progenitor Cells (NPCs) and forebrain cortical neurons (FCNs), and test functional alterations in the Wnt signaling in ADHD and its possible association with affected neurodevelopment seen in patients. Concomitantly, the hypothesis that MPH activates this pathway, while alleviating maturational delays, will be tested. To do so, luciferase reporter assays will be performed in both groups to analyze Wnt activation following treatment, whereas growth rates of iPSCs and NPCs and neuronal synaptogenesis will be measured in xCELLigence/Wst-1 assays and immunocytochemistry, respectively. Following the same reasoning, transcriptomics and protein expression of Wnt-related genes and proteins will be assessed in these three developmental stages using qPCR and Western Blot. ADHD and control groups will be compared before and after MPH treatment. Therefore, our results will facilitate in the understanding of the effects of MPH treatment in ADHD at the molecular level in neural cell models, providing a unique window of opportunity to develop strategies, preventive measures and possible new therapeutic targets.

Bartl, J., Link, P., Schlosser, C., Gerlach, M., Schmitt, A., Walitza, S., Riederer, P, Grunblatt, E. (2010). Effects of methylphenidate: the cellular point of view. Atten Defic Hyperact Disord, 2(4), 225-232. doi:10.1007/s12402-010-0039-6

Bartl, J., Mori, T., Riederer, P., Ozawa, H., & Grunblatt, E. (2013). Methylphenidate enhances neural stem cell differentiation. J Mol Psychiatry, 1(1), 5. doi:10.1186/2049-9256-1-5

Gerlach, M., Grunblatt, E., & Lange, K. W. (2013). Is the treatment with psychostimulants in children and adolescents with attention deficit hyperactivity disorder harmful for the dopaminergic system? Atten Defic Hyperact Disord, 5(2), 71-81. doi:10.1007/s12402-013-0105-y

Grossmann, L., Yde Ohki, C. M., Doring, C., Hoffmann, P., Herms, S., Werling, A. M., Walitza, S., Grunblatt, E. (2021). Generation of integration-free induced pluripotent stem cell lines from four pediatric ADHD patients. Stem Cell Res, 53, 102268. doi:10.1016/j.scr.2021.102268

Grunblatt, E., Bartl, J., & Walitza, S. (2018). Methylphenidate enhances neuronal differentiation and reduces proliferation concomitant to activation of Wnt signal transduction pathways. Transl Psychiatry, 8(1), 51. doi:10.1038/s41398-018-0096-8

Grunblatt, E., Nemoda, Z., Werling, A. M., Roth, A., Angyal, N., Tarnok, Z., Thomsen, H., Peters, T., Hinney, A., Hebebrand, J., Lesch, K. P., Romanos, M., Walitza, S. (2019). The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: Association study and meta-analysis. Am J Med Genet B Neuropsychiatr Genet, 180(6), 365-376. doi:10.1002/ajmg.b.32695

Yde Ohki, C. M., Grossmann, L., Alber, E., Dwivedi, T., Berger, G., Werling, A. M., Walitza, S., Grunblatt, E. (2020). The stress-Wnt-signaling axis: a hypothesis for attention-deficit hyperactivity disorder and therapy approaches. Transl Psychiatry, 10(1), 315. doi:10.1038/s41398-020-00999-9

Yde Ohki, C. M., Grossmann, L., Doring, C., Hoffmann, P., Herms, S., Werling, A. M., Walitza, S., Grunblatt, E. (2021). Generation of integration-free induced pluripotent stem cells from healthy individuals. Stem Cell Res, 53, 102269. doi:10.1016/j.scr.2021.102269