title: Haloperidol and Risperidone at high concentrations activate an in vitro inflammatory response of RAW 264.7 macrophage cells by induction of apoptosis and modification of cytokine levels.
abstract: Antipsychotic drugs, such as haloperidol and risperidone, are used in long-term treatment of psychiatric patients and thus increase the risk of obesity and other metabolic dysfunctions. Available evidence suggests that these drugs have pro-inflammatory effect, which contributes to the establishment of endocrine disturbances. However, results yielded by extant studies are inconsistent. Therefore, in this work, we tested the in vitro effects of different high concentrations of haloperidol and risperidone on the activation of isolated macrophages (RAW 264.7 cell line). The results indicated that macrophages were activated by both drugs. In addition, the activation involved an increase in nitric oxide levels and apoptosis events by modulation of caspases 8 and 3 levels and a decrease of the Bcl-2/BAX gene expression ratio. Cells treated with haloperidol and risperidone also presented higher concentrations of inflammatory cytokines (IL-1β, IL-6, TNFα) and low levels of IL-6 anti-inflammatory cytokine in a dose-dependent manner. Despite the limitation of cell line studies based solely on macrophages cells, we suggest that antipsychotic drugs could potentially exacerbate inflammatory processes in peripheral tissues (blood and fat). The continued activation of macrophages could contribute to the development of obesity and other endocrine disturbances caused by the use of antipsychotic drugs.
authors.affiliation: Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Av Roraima 1000, Prédio 21, 97105900, Santa Maria, Brazil.
authors.forename: Ivo Emílio
authors.initials: IE
authors.lastname: da Cruz Jung
authors.affiliation: Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Av Roraima 1000, Prédio 21, 97105900, Santa Maria, Brazil.
authors.forename: Alencar Kolinski
authors.initials: AK
authors.lastname: Machado
authors.affiliation: Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Av Roraima 1000, Prédio 21, 97105900, Santa Maria, Brazil. ibmcruz@hotmail.com.
authors.forename: Ivana Beatrice Mânica
authors.initials: IB
authors.lastname: da Cruz
authors.affiliation: Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Av Roraima 1000, Prédio 21, 97105900, Santa Maria, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Barbisan
authors.affiliation: Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Av Roraima 1000, Prédio 21, 97105900, Santa Maria, Brazil.
authors.forename: Verônica Farina
authors.initials: VF
authors.lastname: Azzolin
authors.affiliation: Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Av Roraima 1000, Prédio 21, 97105900, Santa Maria, Brazil.
authors.forename: Thiago
authors.initials: T
authors.lastname: Duarte
authors.affiliation: Universidade Luterana do Brasil, BR 287, Km 252, Trevo Maneco Pedroso, Boca do Monte, 97020-001, Santa Maria, Brazil.
authors.forename: Marta Maria Medeiros Frescura
authors.initials: MM
authors.lastname: Duarte
authors.affiliation: Instituto do Cérebro, Pontifícia Universidade Católica do Rio Grande do Sul, Av Ipiranga, 6690, 90600-00, Porto Alegre, Brazil.
authors.forename: Pedro Antônio Schmidt
authors.initials: PA
authors.lastname: do Prado-Lima
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Av Roraima 1000, 97105900, Santa Maria, Brazil.
authors.forename: Guilherme Vargas
authors.initials: GV
authors.lastname: Bochi
authors.affiliation: Departament of Psychiatry, Toronto University, 250 College Street, Toronto, ON, M5T 1R8, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Scola
authors.affiliation: Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Av Roraima 1000, Prédio 21, 97105900, Santa Maria, Brazil.|Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Av Roraima 1000, 97105900, Santa Maria, Brazil.
authors.forename: Rafael Noal
authors.initials: RN
authors.lastname: Moresco
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D000067996:RAW 264.7 Cells; D018967:Risperidone / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D016207:Cytokines; D009569:Nitric Oxide; D006220:Haloperidol; D018967:Risperidone
keywords: Antipsychotic drugs; Apoptosis; Cytokines; Endocrine disturbances; Inflammation; Obesity