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Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration.
- Source :
-
Molecular psychiatry [Mol Psychiatry] 2016 Mar; Vol. 21 (3), pp. 328-38. Date of Electronic Publication: 2015 Jun 23. - Publication Year :
- 2016
-
Abstract
- 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-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.
- Subjects :
- Administration, Intranasal
Animals
Arabidopsis Proteins metabolism
Brain cytology
Brain drug effects
Brain metabolism
Corticosterone blood
DNA, Antisense pharmacology
Depression pathology
Disease Models, Animal
Endocytosis drug effects
Exploratory Behavior drug effects
Fluoxetine administration & dosage
Gene Expression Regulation drug effects
Intramolecular Transferases metabolism
Male
Mice
Mice, Inbred C57BL
Neurons drug effects
Neurons metabolism
Phosphopyruvate Hydratase metabolism
Serotonin metabolism
Serotonin Plasma Membrane Transport Proteins metabolism
Time Factors
Antidepressive Agents administration & dosage
Depression drug therapy
RNA, Small Interfering administration & dosage
Serotonin Plasma Membrane Transport Proteins genetics
Sertraline administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5578
- Volume :
- 21
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 26100539
- Full Text :
- https://doi.org/10.1038/mp.2015.80