title: Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration.
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.
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de Investigaciones Científicas), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ferrés-Coy
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de Investigaciones Científicas), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Galofré
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC; UC-CISC-SODERCAN), Santander, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Pilar-Cuéllar
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC; UC-CISC-SODERCAN), Santander, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Vidal
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de Investigaciones Científicas), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Paz
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de Investigaciones Científicas), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Ruiz-Bronchal
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de Investigaciones Científicas), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Campa
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC; UC-CISC-SODERCAN), Santander, Spain.
authors.forename: Á
authors.initials: Á
authors.lastname: Pazos
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense and IIS Hospital 12 de Octubre, Madrid, Spain.
authors.forename: J R
authors.initials: JR
authors.lastname: Caso
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Department of Pharmacology, School of Medicine, Universidad Complutense and IIS Hospital 12 de Octubre, Madrid, Spain.
authors.forename: J C
authors.initials: JC
authors.lastname: Leza
authors.affiliation: n-Life Therapeutics, S.L., Granada, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Alvarado
authors.affiliation: n-Life Therapeutics, S.L., Granada, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Montefeltro
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.|Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC; UC-CISC-SODERCAN), Santander, Spain.
authors.forename: E M
authors.initials: EM
authors.lastname: Valdizán
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de Investigaciones Científicas), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Artigas
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Department of Neurochemistry and Neuropharmacology, IIBB-CSIC (Consejo Superior de Investigaciones Científicas), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Bortolozzi
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D029681:Arabidopsis Proteins / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D016373:DNA, Antisense / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D019751:Intramolecular Transferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D020280:Sertraline / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D029681:Arabidopsis Proteins; D016373:DNA, Antisense; D034741:RNA, Small Interfering; D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine; D012701:Serotonin; D010751:Phosphopyruvate Hydratase; D019751:Intramolecular Transferases; C568454:marneral synthase, Arabidopsis; D020280:Sertraline; D003345:Corticosterone