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Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration

AuthorsFerrés-Coy, Albert ; Galofré, Mireia ; Pilar-Cuéllar, Fuencisla ; Vidal, Rebeca ; Paz, Verónica ; Ruiz-Bronchal, Esther; Campa, Leticia ; Pazos, Ángel ; Montefeltro, Andrés; Valdizán, Elsa M. ; Artigas, Francesc ; Bortolozzi, Analía
Issue Date6-May-2016
PublisherNature Publishing Group
CitationMolecular Psychiatry 21(3): 328-338 (2016)
AbstractMajor depression brings about a heavy socio-economic burden worldwide due to its high prevalence and the low efficacy of antidepressant drugs, mostly inhibiting the serotonin transporter (SERT). As a result, similar to 80% of patients show recurrent or chronic depression, resulting in a poor quality of life and increased suicide risk. RNA interference (RNAi) strategies have been preliminarily used to evoke antidepressant-like responses in experimental animals. However, the main limitation for the medical use of RNAi is the extreme difficulty to deliver oligonucleotides to selected neurons/systems in the mammalian brain. Here we show that the intranasal administration of a sertraline-conjugated small interfering RNA (C-SERT-siRNA) silenced SERT expression/function and evoked fast antidepressant-like responses in mice. After crossing the permeable olfactory epithelium, the sertraline-conjugated-siRNA was internalized and transported to serotonin cell bodies by deep Rab-7-associated endomembrane vesicles. Seven-day C-SERT-siRNA evoked similar or more marked responses than 28-day fluoxetine treatment. Hence, C-SERT-siRNA (i) downregulated 5-HT1A-autoreceptors and facilitated forebrain serotonin neurotransmission, (ii) accelerated the proliferation of neuronal precursors and (iii) increased hippocampal complexity and plasticity. Further, short-term C-SERT-siRNA reversed depressive -like behaviors in corticosterone-treated mice. The present results show the feasibility of evoking antidepressant -like responses by selectively targeting neuronal populations with appropriate siRNA strategies, opening a way for further translational studies.
DescriptionA Ferrés-Coy et al.
Publisher version (URL)https://doi.org/10.1038/mp.2015.80
Identifiersdoi: 10.1038/mp.2015.80
issn: 1359-4184
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