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Effects of modafinil on immunity, neuroinflammation and development of experimental autoimmune encephalomyelitis in mice

Grant number: 13/18921-5
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2014
Effective date (End): April 30, 2017
Field of knowledge:Biological Sciences - Pharmacology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:João Palermo Neto
Grantee:Adriano Zager
Home Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:09/51886-3 - Neuroimmunomodulation: drugs, stress and cytokines on nervous, endocrine and immune systems relationships, AP.TEM
Associated scholarship(s):15/18803-8 - Effects of pharmacological treatment with modafinil on T cell response of patients with type 1 narcolepsy, BE.EP.PD

Abstract

Modafinil is a psychostimulant drug approved for the treatment of excessive daytime sleepiness, narcolepsy, shift work, and sleep apnea. Among the documented but not yet approved uses for modafinil, it was reported as presenting potential therapeutic uses in ADHD, depression, cocaine dependence, schizophrenia, obesity and fatigue in neurodegenerative diseases. Several studies in rodents described the behavioral and neurochemical changes resulting from modafinil treatment, mainly through modulation of dopaminergic and noradrenergic systems. Recent findings have reported that this drug has neuroprotective potential in animal models of neuroinflammation. However, the mechanism of the neuroprotective effect of modafinil as well as the effect of this drug on the peripheral and CNS immune response are still unknown. Thus, the aim of this study is to evaluate, in mice, the effects of treatment with modafinil on peripheral immunity, neuroinflammation and development of experimental autoimmune encephalomyelitis (EAE), the murine model of Multiple Sclerosis. Specifically, we will analyze the phenotype and cytokine production by in vitro peripheral cells and the in vivo response to delayed-type hypersensitivity, the in vitro immune-inflammatory response of CNS cells, as well as the development of clinical symptoms and characterization of infiltrating inflammatory cells during EAE. We also intend to study the role of different cell types involved in the effect of modafinil in the periphery (lymphocytes vs APCs) and CNS (microglia vs astrocytes), as well as the involvement of dopaminergic, noradrenergic and cholinergic receptors in the phenomenon, through the pharmacological blockade of these receptors. Data will be analyzed under a neuroimmune perspective, specifically the interaction among immunity, dopamine and the neurodegenerative diseases, and possibly they may contribute to suggest therapeutic alternatives. (AU)

Scientific publications (4)
(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)
BRANDAO, WESLEY NOGUEIRA; ANDERSEN, MONICA LEVY; PALERMO-NETO, JOAO; PERON, JEAN PIERRE; ZAGER, ADRIANO. Therapeutic treatment with Modafinil decreases the severity of experimental autoimmune encephalomyelitis in mice. International Immunopharmacology, v. 75, OCT 2019. Web of Science Citations: 0.
BARRETO, TALITA ROSSETTO; COSTOLA-DE-SOUZA, CAROLINA; MARGATHO, RAFAEL OLIVEIRA; QUEIROZ-HAZARBASSANOV, NICOLLE; RODRIGUES, SANDRA CAMPOS; FELICIO, LUCIANO FREITAS; PALERMO-NETO, JOAO; ZAGER, ADRIANO. Repeated Domperidone treatment modulates pulmonary cytokines in LPS-induced acute lung injury in mice. International Immunopharmacology, v. 56, p. 43-50, MAR 2018. Web of Science Citations: 6.
ZAGER, ADRIANO; BRANDAO, WESLEY NOGUEIRA; MARGATHO, RAFAEL OLIVEIRA; GIMENES CRUZ, DANIEL SANZIO; PERON, JEAN PIERRE; TUFIK, SERGIO; ANDERSEN, MONICA LEVY; MORESCO, MONICA; PIZZA, FABIO; PLAZZI, GIUSEPPE; KORNUM, BIRGITTE RAHBEK; PALERMO-NETO, JOAO. Increased interferon-mediated immunity following in vitro and in vivo Modafinil treatment on peripheral immune cells. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 81, p. 297-305, FEB 2 2018. Web of Science Citations: 2.
ZAGER, ADRIANO; BRANDAO, WESLEY NOGUEIRA; MARGATHO, RAFAEL OLIVEIRA; PERON, JEAN PIERRE; TUFIK, SERGIO; ANDERSEN, MONICA LEVY; KORNUM, BIRGITTE RAHBEK; PALERMO-NETO, JOAO. The wake-promoting drug Modafinil prevents motor impairment in sickness behavior induced by LPS in mice: Role for dopaminergic D1 receptor. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 81, p. 468-476, FEB 2 2018. Web of Science Citations: 7.

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