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

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-Iß 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-Iß 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.

Chemogenomics and bioinformatics approaches for prioritizing kinases as drug targets for neglected tropical diseases.

Neglected tropical diseases (NTDs) are a group of twenty-one diseases classified by the World Health Organization that prevail in regions with tropical and subtropical climate and affect more than one billion people. There is an urgent need to develop new and safer drugs for these diseases. Protein kinases are a potential class of targets for developing new drugs against NTDs, since they play crucial role in many biological processes, such as signaling pathways, regulating cellular communication, division, metabolism and death. Bioinformatics is a field that aims to organize large amounts of biological data as well as develop and use tools for understanding and analyze them in order to produce meaningful information in a biological manner. In combination with chemogenomics, which analyzes chemical-biological interactions to screen ligands against selected targets families, these approaches can be used to stablish a rational strategy for prioritizing new drug targets for NTDs. Here, we describe how bioinformatics and chemogenomics tools can help to identify protein kinases and their potential inhibitors for the development of new drugs for NTDs. We present a review of bioinformatics tools and techniques that can be used to define an organisms kinome for drug prioritization, drug and target repurposing, multi-quinase inhibition approachs and selectivity profiling. We also present some successful examples of the application of such approaches in recent case studies.