Neuroprotective effects of dimethyl fumarate against depression-like behaviors via astrocytes and microglia modulation in mice: possible involvement of the HCAR2/Nrf2 signaling pathway.

Autor: de Souza AG; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil. alanagomesdesouza@gmail.com., Lopes IS; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil., Filho AJMC; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil., Cavalcante TMB; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil., Oliveira JVS; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil., de Carvalho MAJ; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil., de Lima KA; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil., Jucá PM; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil., Mendonça SS; Laboratory for Molecular Modeling and Drug Design - LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil., Mottin M; Laboratory for Molecular Modeling and Drug Design - LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil., Andrade CH; Laboratory for Molecular Modeling and Drug Design - LabMol, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil., de Sousa FCF; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil., Macedo DS; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil., de França Fonteles MM; Neuropharmacology Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculdade de Medicina, Universidade Federal do Ceará, Street: Cel. Nunes de Melo 1000, Fortaleza, Ceará, 60431-270, Brazil.; Pharmacy Department, Faculdade de Farmácia, Odontologia e Enfermagem, Universidade Federal do Ceará, Fortaleza, Ceará, Brazil.
Jazyk: angličtina
Zdroj: Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 2022 Sep; Vol. 395 (9), pp. 1029-1045. Date of Electronic Publication: 2022 Jun 04.
DOI: 10.1007/s00210-022-02247-x
Abstrakt: We postulated that dimethyl fumarate (DMF) exerts neuroprotective effects against depression-like behaviors through astrocytes and microglia modulation. To ascertain our hypothesis and define the mechanistic pathways involved in effect of DMF on neuroinflammation, we used the depression model induced by chronic unpredictable mild stress (CUMS), in which, the mice were exposed to stressful events for 28 days and from the 14th day they received DMF in the doses of 50 and 100 mg/kg or fluoxetine 10 mg/kg or saline. On the 29th day, the animals were subjected to behavioral tests. Microglia (Iba1) and astrocyte (GFAP) marker expressions were evaluated by immunofluorescence analyzes and the cytokines TNF-α and IL-Iβ by immunoenzymatic assay. In addition, computational target prediction, 3D protein structure prediction, and docking calculations were performed with monomethyl fumarate (DMF active metabolite) and the Keap1 and HCAR2 proteins, which suggested that these could be the probable targets related protective effects. CUMS induced anxiety- and depressive-like behaviors, cognitive deficit, decreased GFAP, and increased Iba1, TNF-α, and IL-Iβ expression in the hippocampus. These alterations were reversed by DMF. Thus, it is suggested that one of the mechanisms involved in the antidepressant effect of DMF is neuroinflammatory suppression, through the signaling pathway HCAR2/Nrf2. However, more studies must be performed to better understand the molecular mechanisms of this drug.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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