Journal Article

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

Vidal, R, Ferrés-Coy, A, Caso, J R, Bortolozzi, A, Galofré, M, Alvarado, G, Paz, V, Montefeltro, A, Pilar-Cuéllar, F, Valdizán, E M, Leza, J C, Campa, L, Pazos, Á, Artigas, F, Ruiz-Bronchal, E

2016

Overview

Major 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, ~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-HT 1A -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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/89 / 14/63 / 64/60 / 692/699/476/1414 / Administration, Intranasal / Animals / Antidepressants / Antidepressive Agents - administration & dosage / Arabidopsis Proteins - metabolism / Behavioral Sciences / Biological Psychology / Brain - cytology / Brain - drug effects / Brain - metabolism / Care and treatment / Complications and side effects / Corticosterone - blood / Depression - drug therapy / Depression - pathology / Disease Models, Animal / DNA, Antisense - pharmacology / Dosage and administration / Drugs / Endocytosis - drug effects / Exploratory Behavior - drug effects / Fluoxetine - administration & dosage / Gene Expression Regulation - drug effects / Intramolecular Transferases - metabolism / Major depressive disorder / Male / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Neurochemistry / Neurons - drug effects / Neurons - metabolism / Neurosciences / Original / original-article / Pharmacotherapy / Phosphopyruvate Hydratase - metabolism / Psychiatry / Risk factors / RNA, Small Interfering - administration & dosage / Serotonin / Serotonin - metabolism / Serotonin Plasma Membrane Transport Proteins - genetics / Serotonin Plasma Membrane Transport Proteins - metabolism / Sertraline - administration & dosage / Time Factors