title: Direct inhibition of retinoic acid catabolism by fluoxetine.
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.
authors.affiliation: Department of Psychiatry, Section Clinical Neurobiology, Campus Benjamin Franklin, Charité, University Medicine Berlin, Hindenburgdamm 30, 12203, Berlin, Germany, julian.hellmann@charite.de.
authors.forename: Julian
authors.initials: J
authors.lastname: Hellmann-Regen
authors.forename: Ria
authors.initials: R
authors.lastname: Uhlemann
authors.forename: Francesca
authors.initials: F
authors.lastname: Regen
authors.forename: Isabella
authors.initials: I
authors.lastname: Heuser
authors.forename: Christian
authors.initials: C
authors.lastname: Otte
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.forename: Golo
authors.initials: G
authors.lastname: Kronenberg
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D000077408:Modafinil; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001559:Benzhydryl Compounds; D018696:Neuroprotective Agents; D018168:Receptors, Retinoic Acid; D005473:Fluoxetine; D018698:Glutamic Acid; D014212:Tretinoin; D003975:Diazepam; D000077408:Modafinil