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.

Enhancement of Local Retionic Acid Signaling: A Pivotal Mechanism in Fluoxetine's Pleiotropic Actions

“…Therefore, a local interaction in the brain may be of relevance for local RA concentrations as well. Most interestingly, we were able to demonstrate this relationship in a series of previous experiments, indicating a direct inhibitory effect of fluoxetine on local RA degradation in brain tissue 8 , pointing towards altered RA-signaling as a putative missing link between the multiple, RA-like (and serotonin-independent) effects of fluoxetine. RA is a crucial CNS morphogen, involved in patterning and neuronal differentiation in embryonic brain development, but also an essential factor in neuronal plasticity and regeneration of the adult CNS 9 .…”

“…At a functional level, we were able to demonstrate that fluoxetine was able to reduce glutamate excitotoxicity on primary neurons to a similar extent observed for RA treatment. This effect was blocked by inhibition of RXRs, but augmented by a pan-RAR blocking agent, suggesting that RA signaling via RXR receptors may predominantly mediate the neuroprotective effects of fluoxetine 8 .…”

Serotonin Depletion Does not Modify the Short-Term Brain Hypometabolism and Hippocampal Neurodegeneration Induced by the Lithium–Pilocarpine Model of Status Epilepticus in Rats

“…Finally, direct actions on enzyme systems may also contribute to the antidepressant and neuroprotective effects of fluoxetine. In this way, direct actions on the acid sphingomyelinase-ceramide system, lowering the ceramide abundance (Gulbins et al 2013) and inhibition of the retinoic acid metabolism (Hellmann-Regen et al 2015) have recently been described. Surprisingly, detrimental effects of fluoxetine in the rat pilocarpine model have also been reported.…”

“…Since SSRI drugs increase the extracellular levels of 5-HT, the above-mentioned findings point to brain 5-HT as a neuroprotective factor in this model of SE. Nevertheless, it has also been reported that non5HTergic mechanisms might participate in some protective actions mediated by fluoxetine (Hellmann-Regen et al 2015;Vizi et al 2013;Wang et al 2003).…”

Anti-inflammatory effects of minocycline are mediated by retinoid signaling

“…Moreover, there is a large body of direct evidence for an involvement of retinoid signaling in the pathogenesis of affective [ 45 ] and of other neuropsychiatric disorders [ 46 ], suggesting that local brain RA may function as an “endogenous antidepressant”. Furthermore, the catabolism of RA [ 47 ] is inhibited by the widely-used and well-established antidepressant fluoxetine, suggesting that fluoxetine’s neuroprotective, its anti-inflammatory—and potentially its anti-depressant properties may all together be mediated through RA signaling [ 48 ].…”