Effect of fluoxetine pretreatment on LPS-induced hypothermia

Author(s)

Isis Paiva Trajano

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2024-03-15

Examining board members

Luiz Guilherme de Siqueira Branco; Glauce Crivelaro do Nascimento Marangoni; Angelita Maria Stabile

• Advisor: Luiz Guilherme de Siqueira Branco; Luís Henrique Angenendt da Costa

Abstract

Syndromes associated with systemic inflammation are accompanied by high mortality and remain a challenge in emergency medicine. The administration of lipopolysaccharide (LPS) experimentally mimics a systemic inflammation that produces pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6, in addition to changes in body temperature, such as fever and hypothermia, depending on dose and room temperature. The high mortality resulting from severe cases of systemic inflammation and the impairment it causes makes understanding the mechanisms involved essential for the discovery of new therapies. Our laboratory recently demonstrated that central administration of exogenous serotonin (5-HT) has an anti-inflammatory effect in an animal model of inflammation. In this sense, we formulate the hypothesis that manipulation of the serotonergic pathway is a potential therapeutic target, with fluoxetine (a selective serotonin reuptake inhibitor - SSRI) being a potential immunomodulator via serotonergic mechanisms. Thus, the aim of this project is to evaluate the possible role of fluoxetine pretreatment on thermoregulatory and neuroimmune parameters in animals with systemic inflammation. For this, animals were pre-treated with fluoxetine for 7 days and subjected to endotoxemia through the administration of LPS on the day of the experiment. Animals were then euthanized to collect plasma, brain, spleen and brown adipose tissue, for the measurement of serum and splenic anti-and pro-inflammatory cytokines, in addition to PGE2 and PGD2 in the hypothalamus and plasma and quantification of UCP. -1 in brown adipose tissue, adding to the measurement of internal body temperature, tail temperature (to calculate the Heat Loss Index) and O2 consumption (to measure thermogenesis without shivering) that were carried out during the experiment. The results showed reduced plasma levels of 5-HT, as well as increased levels of NO and cytokines in plasma and spleen and PGE2 in the hypothalamus during SI. Interestingly, FLX attenuated LPS-induced hypothermia, accompanied by a reduction in splenic and plasma NOs, as well as interleukins (IL) 6 and 10. These data indicate that reduced 5-HT levels during SI are associated with increased pro-inflammatory observed during hypothermia. Additionally, the results align with the hypothesis that hypothermia, blunted by FLX, develops in fact in a regulated form, as an adaptative strategy, and that FLX anti-inflammatory effect is apparently the result from the recruitment of more than one signalling pathway, such as the splenic anti-inflammatory pathway and FLX effect directly upon immune cells. (AU)

• FAPESP's process: 22/01783-8 - Effects of fluoxetine pretreatment on endotoxemia-induced hypothermia
• Grantee: Isis Paiva Trajano
• Support Opportunities: Scholarships in Brazil - Master