Clemens V, Regen F, Hellmann-Regen J. J Neurol Neuromedicine (2016) 1(6): 17-22 Neuromedicine www.jneurology.com www.jneurology.com Journal of Neurology & Neuromedicine Mini Review Open Access Enhancement of Local Retionic Acid Signaling: A Pivotal Mechanism in Fluoxetine’s Pleiotropic Actions Vera Clemens, Francesca Regen, Julian Hellmann-Regen Charité Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychotherapie, Campus Benjamin Franklin, Germany Article Info ABSTRACT Article Notes Major depression (MDD) is one of the leading global causes of all non-fatal Received: May 05, 2016 burden of disease. Involving monoaminergic imbalances, but also hormonal, Accepted: September 13, 2016 structural and inflammatory alterations, the underlying pathogenesis remains *Correspondence: incompletely understood. The antidepressant drug fluoxetine, which may Dr. Julian Hellmann-Regen, Charité Universitätsmedizin Berlin be considered the “prototype” of all selective serotonin reuptake inhibitors Klinik für Psychiatrie und Psychotherapie (SSRI), appears to affect all of these processes. Interestingly, this is also the Campus Benjamin Franklin case for retinoic acid (RA), the highly potent active metabolite of vitamin Hindenburgdamm 30 A. In this review, we discuss RA signaling as a central mechanism of action 12203 Berlin, Germany – and missing link – for the multiple, pleiotropic effects of fluoxetine in the E-mail: [email protected] CNS, suggesting that direct inhibition of CYP-450-mediated RA catabolism by © 2016 Hellmann-Regen J. This article is distributed under the fluoxetine results in increased local concentration, and enhanced paracrine terms of the Creative Commons Attribution 4.0 International RA signaling in the CNS. License Keywords: Major Depression Vitamin A Introduction Retinoic acid Mental and substance use disorders are the leading global cause of Fluoxetine Cytochrome P450 all non-fatal burden of disease with major depressive disorder (MDD) having the biggest impact in this group1. While the neurobiological mechanisms underlying MDD are highly complex and not yet serendipity discovered, started over 50 years ago. Revelation of a fully understood, treatment with antidepressant substances, first to the neurobiological understanding of MDD pathogenesis and led tocommon the “monoamine monoaminergic hypothesis” mode of2 action has significantly contributed selective serotonin reuptake inhibitor (SSRI) that was approved by the Food and Drug Administration. Fluoxetine, (FDA) which in 1987, was themay first be considered the “prototype” of all modern, selective monoaminergic antidepressants. Although numerous substances with a selective monoaminergic mechanism of action have followed and been Fluoxetine, but also other selective monoaminergic antidepressants, doapproved not exhibit since, fluoxetineany immediate is still effectivelyantidepressant used in actions. clinical practice.In fact, antidepressant action is known to occur no earlier than 2-3 weeks after onset of treatment, a fact suggesting other processes, secondary to (altered) monoaminergic signaling, to be responsible for and involved in an antidepressant mechanism of action. Therefore, many additional theories about fluoxetine’s antidepressant mode of action ofare synaptic discussed. plasticity Several in specific, hippocampal but likely neurons “serotonin-independent”3,4 mechanismseffects of fluoxetine5, but also have a been serotonin-independent demonstrated, including effect enhancement on the acid sphingomyelinase-ceramide system6,7. , anti-inflammatory Page 17 of 22 Clemens V, Regen F, Hellmann-Regen J. J Neurol Neuromedicine (2016) 1(6): 17-22 Journal of Neurology & Neuromedicine Interestingly, one of the hallmark characteristics of RA Signaling in MDD RA is involved in several MDD related processes, which interact strongly with the cytochrome P450 (CYP450)- is most strikingly demonstrated in a knockout mouse, systemfluoxetine30. While is its this rather fact haslong mainly half-life been and of interestits ability in theto context of drug-drug interactions, it is noteworthy that like behavior in the mice16,17. CYP450 enzymes are rather ubiquitously expressed, also where, ablation of RXRγ was found to lead to depressive- (or especially) in the brain, where they are believed to Moreover, chronic treatment with isoretinoin, the 13-cis-isomer and prodrug of retinoic acid that is used in acne therapy, is well known to cause severe depressive contributeThe metabolism to specific of retinoidslocal small molecule levels. symptoms including suicide18. Given the tight regulation Retinoic acid (RA), the active metabolite of Vitamin A, of RA homeostasis by local synthesis and differential local is one of the most important, CNS-active small molecules regulated by local CYP450-catabolism. As mentioned surprising that opposite effects can be observed for chronic, high-dosedegradation treatment via fine-tuned with retinoids feedback (inducingmechanisms, depressive- it is not degrading CYP450-isozymes30. Therefore, a local interaction like behavior) and for acute, short-term treatment, which inabove, the brain fluoxetine may be is knownof relevance to inhibit for local a number RA concentrations of likely RA- was reported to have antidepressive effects similar to those as well. Most interestingly, we were able to demonstrate 17. this relationship in a series of previous experiments, observedDuring for embry fluoxetineonic development, a negative feedback was shown for RA on the expression of ROLDHs and 8 RA degradation in brain tissue , pointing towards altered thereby its own synthesis19. In almost all other developing indicating a direct inhibitory effect of fluoxetine on local RA-signaling as a putative missing link between the or adult tissues, local degradation of RA via CYP450- multiple, RA-like (and serotonin-independent) effects enzymes is positively feedback-regulated by RA with RAR involvement20,21. Several isozymes of CYP450, including in patterning and neuronal differentiation in embryonic brainof fluoxetine. development, RA is but a crucialalso an essentialCNS morphogen, factor in neuronalinvolved 9 plasticity and regeneration of the adult CNS . RA belongs to inretinoid RA-catabolism specific 22,23CYP26. While isozymes in adults butCYP26A1 also lessis mainly well the group of endogenous retinoids, which are metabolites expressedcharacterized in theones, liver, have CYP26B1 been identifiedhas been toshown be involved to have of retinol and other precursors termed “vitamin A” or the highest levels in the CNS24,25. Highlighting the clinical beta-carotene. After oral uptake, vitamin A-derivatives are impact of the CYP450-system in the context of MDD, an stored as retinyl esters, mainly in the liver10. Transport to association has been found between functionally relevant tissue targets takes place via the blood as retinol bound to polymorphisms of RA-catabolizing CYP450-isozymes, such retinol-binding protein (RBP)11. Uptake into the target cells as CYP2C19, on the one hand, and response to antidepressant has been demonstrated to involve binding to membrane treatment26 as well as prevalence of depressive symptoms receptor STRA612. Subsequently, retinol is oxidized by and risk for depression and suicide itself on the other hand the retinol dehydrogenase (ROLDH) into retinal and in a 27,28. Consequently, transgenic mice expressing the mutant second step via retinaldehyde dehydrogenase (RALDH) human CYP2C19 gene were found to exhibit hippocampal atrophy and depressive-like symptoms29. Against the other, neighboring cells, generating “RA gradients”, which background of RA´s involvement in MDD pathogenesis and againinto RA, depend the final not onlyactive on metabolite the local ratewhich of cansynthesis, diffuse but to its catabolism via CYP450-isozymes, RA signaling might more importantly on the local rates of degradation via represent a missing link between pathologically increased the CYP450-system. Resembling a central, endogenous catabolism (e.g. via aberrant CYP2C19 isoforms) and neurotrophic process, an involvement of altered RALDH altered state of mood and behavior. function has been suggested by Gruenblatt and Riederer to play a role in the pathogenesis of neurodegenerative Common targets of fluoxetine and RA in MDD disorders such as Alzheimers‘ disease at the genetic, Fluoxetine and RA exhibit several effects in common protein expression level and at the level of enzymatic on MDD related processes, supporting the hypothesis activity13 ofenhanced RA signaling as an underlying mechanism for binding to cellular retinoic acid binding protein (CRABP) I and II, .CRABP With respectII assists to RA RA’s to entermolecular the nucleus actions, and after to Synaptic plasticity including structural and functional reach its nuclear receptors14. RA binds to retinoic acid fluoxetine’s serotonin-independent pleiotropic effects. beprocesses affected in during neurons MDD due pathogenesis to environmental31,32. Interestingly, influences responsereceptors (RARα,elements RARβ (RARE), and RARγ) inducing and retinoic ligand-dependent X receptors RAsuch signaling as injury, canstress directly and inflammation, affect homeostatic is well knownsynaptic to transcription(RXRα, RXRβ 15and. RXRγ) which in turn bind to retinoic acid plasticity via RARα and the Calcium-dependent protein Page 18 of 22 Clemens V, Regen F, Hellmann-Regen J. J Neurol Neuromedicine (2016) 1(6): 17-22 Journal of Neurology & Neuromedicine Figure 1: Retinoid homeostasis and involvement in MDD-related