Effect of fluvoxamine on neuroimmune alterations in septic rats

• Grant number: 19/27231-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2020
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Guilherme de Siqueira Branco
• Grantee: Luís Henrique Angenendt da Costa
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 16/17681-9 - Pathophysiological changes during systemic inflammation, AP.TEM
• Associated scholarship(s): 22/12780-0 - Hypothermia as a therapeutic strategy for ischemic stroke, BE.EP.PD

Abstract

Sepsis, an organic dysfunction resulting from a dysregulated response to an infection, has a complex pathophysiology, mainly associated with the excessive production of inflammatory mediators. These mediators have deleterious actions to the body, not only in the acute phase of the disease, but also promote persistent changes in those who survive Sepsis, such as cognitive and memory deficits. Given the high mortality in Sepsis and the neurological impairment it causes, it is necessary to investigate innovative and broad-spectrum therapies. In this sense, we believe that manipulation of the serotonergic pathway is a potential treatment target. We have recently demonstrated that central administration of serotonin (5-HT) has an anti-inflammatory effect on systemic inflammation, suggesting that a treatment that increases 5-HT bioavailability may be beneficial in Sepsis. A possible candidate would be fluvoxamine (FLV), a commercially available serotonin reuptake inhibitor. In addition to increasing central and peripheral 5-HT bioavailability, fluvoxamine may also exert serotonin-independent anti-inflammatory actions by binding to the sigma-1 receptor (S1R) present in the endoplasmic reticulum of several immune cells, regulating the cytokine production. However, there are no reports on the action of FLV on neuroinflammation caused by Sepsis or its possible benefits on cognitive impairment in survivors. Thus, our first objective is to evaluate the role of FLV treatment on neuroimmune parameters in animals undergoing Sepsis induced by Cecum Ligation and Puncture (CLP), a clinically relevant model of the disease. We will also elucidate the functional consequences of this treatment by evaluating the role of FLV on memory and behavioral deficits in Sepsis-surviving animals. In order to investigate the possible pathways of action of this drug, we will separately assess the role of central and peripheral serotonin in regulating the immune response with the use of fluvoxamine. And finally, given the dual action mechanism of this treatment, we will investigate the relationship between sigma-1 receptor action on glial cells (astrocytes and microglia) and the effects of FLV on the production of central inflammatory mediators by these cells. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

COSTA, LUIS H. A.; SANTOS, BRUNA M.; BRANCO, LUIZ G. S.. Can selective serotonin reuptake inhibitors have a neuroprotective effect during COVID-19?. European Journal of Pharmacology, v. 889, DEC 15 2020. (19/27231-9, 16/17681-9)