title: A novel isoquinoline compound abolishes chronic unpredictable mild stress-induced depressive-like behavior in mice.
abstract: Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1mg/kg, intragastric) or paroxetine (8mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [(3)H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [(3)H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression.
authors.affiliation: Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Pesarico
authors.affiliation: Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Gláubia
authors.initials: G
authors.lastname: Sartori
authors.affiliation: Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: César A
authors.initials: CA
authors.lastname: Brüning
authors.affiliation: Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Anderson C
authors.initials: AC
authors.lastname: Mantovani
authors.affiliation: Programa de Pós-graduação em Farmacologia, Universidade Federal de Santa Maria, CEP 97105-900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Thiago
authors.initials: T
authors.lastname: Duarte
authors.affiliation: Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Gilson
authors.initials: G
authors.lastname: Zeni
authors.affiliation: Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900 Santa Maria, Rio Grande do Sul, Brazil. Electronic address: criswn@ufsm.br.
authors.forename: Cristina Wayne
authors.initials: CW
authors.lastname: Nogueira
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D006120:Grooming / Q000187:drug effects; D019417:Hindlimb Suspension / Q000523:psychology; D006728:Hormones / Q000378:metabolism; D008124:Locomotion; D008297:Male; D051379:Mice; D017374:Paroxetine / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D012701:Serotonin / Q000493:pharmacokinetics; D013315:Stress, Psychological / Q000150:complications*; D013550:Swimming / Q000523:psychology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C000614591:7-fluoro-1,3-diphenylisoquinoline-1-amine; D000928:Antidepressive Agents; D016207:Cytokines; D006728:Hormones; D011804:Quinolines; D014316:Tritium; D012701:Serotonin; D017374:Paroxetine
keywords: Antidepressant; BDNF; Chronic unpredictable mild stress; Inflammation; Isoquinoline; Serotonin