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Grant support

We thank Maria Calvo, Elisenda Coll and Anna Bosch for outstanding technical support in the Confocal microscopy unit (CCiT-UB) and Maria C Carmona for advice on design of small RNA and oligonucleotidc molecules. This work was supported by grants from CDTI-Spanish Ministry of Science and Innovation-DENDRIA contribution, 'nLife all rights reserved' (to AB and FA); Institute de Salud Carlos III PI10/00290 and PI13/01390 (to AB), PI/10/0123 (to JCL) and Centro de Investigation Biomedica en Red de Salud Mental (CIBERSAM); NARSAD Independent Investigator Grant from the Brain & Behavior Research Foundation Grant 20003 (to AB); Ministry of Economy and Competitiveness SAF2012-35183 (to FA) and SAF2011-25020 (to AP); and Generalitat de Catalunya, Secretaria d'Universitat i Recerca del Departament &Economia i Coneixement (SGR2014) Catalan Government Grant 2009SGR220 (to FA). Some of these grants are co-financed by the European Regional Development Fund 'A way to build Europe'. AF-C is a recipient of a fellowship from Spanish Ministry of Education, Culture and Sport.

Analysis of institutional authors

Ferres-Coy, AAuthorGalofre, MAuthorPaz, VAuthorRuiz-Bronchal, EAuthorCampa, LAuthorArtigas, FAuthorBortolozzi, ACorresponding Author

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November 6, 2015
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Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration

Publicated to:Molecular Psychiatry. 21 (3): 328-338 - 2016-03-01 21(3), DOI: 10.1038/mp.2015.80

Authors: Ferres-Coy, A; Galofre, M; Pilar-Cuellar, F; Vidal, R; Paz, V; Ruiz-Bronchal, E; Campa, L; Pazos, A; Caso, J R; Leza, J C; Alvarado, G; Montefeltro, A; Valdizan, E M; Artigas, F; Bortolozzi, A

Affiliations

IIBB CSIC Consejo Super Invest Cient, Dept Neurochem & Neuropharmacol, Barcelona, Spain      Consejo Superior de Investigaciones Cientificas (CSIC) - Author
IIBB CSIC IDIBAPS, Dept Neurochem & Neuropharmacol, Rossello 161,6th Floor, Barcelona 08036, Spain.      Hospital Clinic de Barcelona    Consejo Superior de Investigaciones Cientificas (CSIC)    University of Barcelona    IDIBAPS - Author
IIS Hosp 12 Octubre, Madrid, Spain       - Author
Inst Biomed & Biotechnol Cantabria IBBTEC UC CSIC, Santander, Spain      CSIC - Instituto de Biomedicina y Biotecnologia de Cantabria (IBBTEC)    Consejo Superior de Investigaciones Cientificas (CSIC) - Author
Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain      Hospital Clinic de Barcelona    IDIBAPS    University of Barcelona - Author
ISCIII, Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain      CIBERSAM    CIBER - Centro de Investigacion Biomedica en Red - Author
n Life Therapeut SL, Granada, Spain - Author
Univ Complutense, Sch Med, Dept Pharmacol, E-28040 Madrid, Spain      Complutense University of Madrid       - Author
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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.

Keywords

antisensedeliveryendocytosisfluoxetineinvolvementmaturationmechanismsneurogenesisreceptorsAdministration, intranasalAnimalsAntidepressive agentsArabidopsis proteinsBrainCorticosteroneDepressionDisease models, animalDna, antisenseEndocytosisExploratory behaviorFluoxetineGene expression regulationIntramolecular transferasesMajor depressionMaleMarneral synthase, arabidopsisMiceMice, inbred c57blNeuronsPhosphopyruvate hydrataseRna, small interferingSerotoninSerotonin plasma membrane transport proteinsSertralineTime factors

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Molecular Psychiatry due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2016, it was in position 7/290, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry & Molecular Biology.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.08. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 6.66 (source consulted: Dimensions Aug 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-08-02, the following number of citations:

  • WoS: 41
  • Scopus: 32
  • Europe PMC: 29
  • Google Scholar: 61

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-08-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 128.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 130 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 132.75.
  • The number of mentions on the social network Facebook: 2 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 7 (Altmetric).
  • The number of mentions in news outlets: 17 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Granada.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Ferres Coy, Albert) and Last Author (Bortolozzi Biassoni, Analía).

the author responsible for correspondence tasks has been Bortolozzi Biassoni, Analía.