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Direct inhibition of retinoic acid catabolism by fluoxetine

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

Recent evidence from animal and human studies suggests neuroprotective effects of the SSRI fluoxetine, e.g., in the aftermath of stroke. The underlying molecular mechanisms remain to be fully defined. Because of its effects on the cytochrome P450 system (CYP450), we hypothesized that neuroprotection by fluoxetine is related to altered metabolism of retinoic acid (RA), whose CYP450-mediated degradation in brain tissue constitutes an important step in the regulation of its site-specific auto- and paracrine actions. Using traditional pharmacological in vitro assays, the effects of fluoxetine on RA degradation were probed in crude synaptosomes from rat brain and human-derived SH-SY5Y cells, and in cultures of neuron-like SH-SY5Y cells. Furthermore, retinoid-dependent effects of fluoxetine on neuronal survival following glutamate exposure were investigated in rat primary neurons cells using specific retinoid receptor antagonists. Experiments revealed dose-dependent inhibition of synaptosomal RA degradation by fluoxetine along with dose-dependent increases in RA levels in cell cultures. Furthermore, fluoxetine’s neuroprotective effects against glutamate excitotoxicity in rat primary neurons were demonstrated to partially depend on RA signaling. Taken together, these findings demonstrate for the first time that the potent, pleiotropic antidepressant fluoxetine directly interacts with RA homeostasis in brain tissue, thereby exerting its neuroprotective effects.

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Acknowledgments

JHR is participant in the Charité Clinical Scientist Program funded by the Charité Universitätsmedizin Berlin and the Berlin Institute of Health. This work was further supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich TRR 43 and Cluster of Excellence 257 NeuroCure), the Bundesministerium für Bildung und Forschung (Center for Stroke Research Berlin) and the DZHK (German Center for Cardiovascular Research), Berlin partner site.

Conflict of interest

CO has received honoraria fees for lectures from Lundbeck and Servier and has received compensation as a member of the scientific advisory board of Lundbeck. ME received grant support from AstraZeneca, Sanofi and Roche; participated in advisory board meetings of Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, MSD, Pfizer, Sanofi; and received honoraria from Astra Zeneca, Bayer, Boston Scientific, Berlin Chemie, Bristol-Myers Squibb, Boehringer-Ingelheim, Desitin, Ever, Glaxo Smith Kline, MSD, Novartis, Pfizer, Sanofi, Servier and Takeda. G.K. received honoraria from Eli Lilly.

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    1. Department of Psychiatry, Section Clinical Neurobiology, Campus Benjamin Franklin, Charité, University Medicine Berlin, Hindenburgdamm 30, 12203, Berlin, Germany

      Julian Hellmann-Regen, Francesca Regen, Isabella Heuser & Christian Otte

    2. Department of Neurology, Section Experimental Neurology, Campus Charité Mitte, Charité, University Medicine Berlin, Berlin, Germany

      Matthias Endres, Karen Gertz & Golo Kronenberg

    3. Department of Psychiatry, Campus Charité Mitte, Charité, University Medicine Berlin, Berlin, Germany

      Ria Uhlemann & Golo Kronenberg

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    1. Julian Hellmann-Regen
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    Correspondence to Julian Hellmann-Regen.

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    K. Gertz and G. Kronenberg contributed equally to this work.

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    Hellmann-Regen, J., Uhlemann, R., Regen, F. et al. Direct inhibition of retinoic acid catabolism by fluoxetine. J Neural Transm 122, 1329–1338 (2015). https://doi.org/10.1007/s00702-015-1407-3

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