PPAR-γ agonist GL516 reduces oxidative stress and apoptosis occurrence in a rat astrocyte cell line. (June 2019) - Giampietro, Letizia
Abstract: Aims: The worldwide increase in aging population is prevalently associated with the increase of neurodegenerative diseases. Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-modulated transcriptional factors which belong to the nuclear hormone receptor superfamily which regulates peroxisome proliferation. The PPAR-γ is the most extensively studied among the three isoforms and the neuroprotective effects of PPAR-γ agonists have been recently demonstrated in a variety of preclinical models of neurological disorders. The aim of the study is to biologically evaluate the neuroprotective effects of new PPAR-γ selective agonists in an in vitro model. Main methods: CTX-TNA2 rat astrocytes were treated with G3335, a PPAR-γ antagonist, to simulate the conditions of a neurological disorder. Newly synthetized PPAR-γ selective agonists were added to the cell culture. Cytotoxicity was assessed by MTT assay, catalase activity was investigated by a colorimetric assay, Reactive Oxygen Species (ROS) production and apoptosis occurrence were measured by flow cytometry. Western blotting were performed to measure the levels of protein involved in the apoptotic pathway. Key findings: Four PPAR-γ agonists were selected. Among them, the GL516, a fibrate derivative, showed low cytotoxicity and proved effective in restoring the catalase activity, reducing ROS production and decreasing the apoptosis occurrence triggered by the G3335 administration. The effects of this molecule appear to be comparable to the reference compound rosiglitazone, a potent and selective PPAR-γ agonist, mainly at prolonged exposure times (96 h). Significance: Based on recent evidence, hypofunctionality of the PPAR-γ in glial cells could be present in neurodegenerative diseases and could participate in pathological mechanisms through peroxisomal damage. The fibrate derivative PPAR-γ agonist GL516 emerged as the most promising molecule of the series and could have a role in preventing the pathophysiology of neurodegenerative disorders. Graphical abstract: Image 1 Highlights: Four novel PPAR-γ agonists restored catalase activity in an astrocyte cell line treated with the PPAR-γ antagonist G3335. Among them, the GL516, a fibrate derivative, showed low cytotoxicity and was selected for further analyses. The GL516 modulates oxidative stress and apoptosis in astrocytes. The new PPAR agonist GL516 proved to have neuroprotective properties.