Planta Med 2011; 77 - SL34
DOI: 10.1055/s-0031-1282157

Comparative analysis of gene expression profiles from rats treated with a standardized willow bark preparation, its salicin rich ethanol fraction and imipramine for toxicological endpoints

G Ulrich Merzenich 1, A Koptina 1, O Kelber 2, A Freischmidt 3, J Heilmann 3, J Müller 2, H Zeitler 4, D Panek 4, H Winterhoff 5
  • 1Medical Policlinic and Clinic III, Universitätsklinikum, Rhein. Friedrich-Wilhelms University Bonn, Bonn, Germany
  • 2Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany
  • 3Pharmaceutical Biology, University of Regensburg, Regensburg, Germany
  • 4Medical Policlinic and Clinic I, Universitätsklinikum, Rhein. Friedrich-Wilhelms University Bonn, Bonn, Germany
  • 5Institut of Pharmacology and Toxicology, Westfälische Wilhelms-University, Münster, Germany

We reported earlier that the treatment of CD-rats with a standardized willow bark extract (WB) or its salicin rich ethanol fraction (EtOHFr.) (1) showed antidepressant like effects comparable to the tricyclic antidepressant imipramine in the Porsolt Swimming test (2). Corresponding gene expression profiles were further investigated for potential toxicological endpoints.

Gene expression profiles (Agilent Whole Genome Array, n=4/group) obtained from peripheral blood of male Sprague Dawley rats treated with WB (STW-33–1), the EtOHFr. (30mg/kg bw) or imipramine (20mg/kg bw) as described (2,3) were comparatively analysed by the Ingenuity Systems Programme, which allows to conduct model calculations of tresholds for theoretical toxic endpoints.

The three treatments related to 47 disease clusters. The WB extract reached the treshold for a potential side effect once (cardiac hypertrophy), whereas the EtOHFr exceeded the treshold in 5 disease clusters (cardiac arteriopathy and stenosis, glomerular Injury, pulmonary hypertension). Disease clusters hit by imipramine↑alkaline phosphatase levels treatment (13) matched widely its reported side effects: cardiovascular system: tachykardia, palpitation, myocardial infarction, arrhythmias, heart block, precipitation of congestive heart failure; urinary retention, altered liver functions. Glomerular injury and altered liver functions are part of the side effect profile of aspirin in agreement with the findings for the salicin rich EtOHFr.

The applied method appears to be useful for predictions of potential side effects. The phenomena that the WB extract, being effective, reached only once a potential „toxic endpoint“ should be further investigated. It questions the commonly assumed principle that substances without side effects will have a poor efficacy.

Keywords: Willow bark, Imipramine, gene expression, side effects, prediction

Acknowledgement: Dr. Anna Koptina is presently holding a scholarship of the DAAD (German academic exchange service). Parts of the work were supported by Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany.

References: 1. Bonaterra GA et al. (2010) Phytomedicine 17(4): 1106–13

2. Ulrich-Merzenich G et al. (2009) Planta MedSL53

3. Ulrich-Merzenich G et al. (2009) Z.f. Phytotherapie 30 (Suppl 1) S16