Effects of the PPAR-β agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination

Abstract

BackgroundBrain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-β seems to play an important role in the regulation of central inflammation. In addition, PPAR-β agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-β agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-γ and LPS.MethodsAggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-γ and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-β, PPAR-γ, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling.ResultsGW 501516 decreased the IFN-γ-induced up-regulation of TNF-α and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-β agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression.ConclusionAlthough GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-β agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.

Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice

“…Notably, a PPARβ/δ-dependent inhibition of Tnfa mRNA was observed in Kupffer cells, and this effect did not require binding of PPARβ/δ to its cognate DNA binding domain as shown by examination of transgenic mice expressing a PPARβ/δ DBM. These results support numerous studies showing that PPARβ/δ suppresses inflammation in the liver (Lee et al 2012; Lim et al 2009; Sanderson et al 2010; Shan et al 2008a; Shan et al 2008b) and in other models (Barish et al 2008; Collino et al 2011; Defaux et al 2009; Haskova et al 2008; Salvado et al 2014). However, they markedly extend previous studies by suggesting that PPARβ/δ expression in Kupffer cells is required to modulate the anti-inflammatory and chemopreventive activity observed in HBV transgenic mice, and that this is mediated through a mechanism that does not require binding to its cognate DNA binding element found in its target genes.…”

Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

“…For instance, pharmacological activation of PPAR β / δ in rat aggregating brain cells cultures with the synthetic compound GW501516 decreased IFN γ -induced TNF α and INOS in a similar manner to what has been reported in isolated cultures [199]. Further supporting anti-inflammatory function for PPAR β / δ , oral administration of the selective PPAR β / δ agonist GW0742 in a mouse of experimental autoimmune encephalomyelitis, reduced astroglial and microglial inflammatory activation as well as IL-1 β levels in brain [200].…”

Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease

“…The actions of another nuclear receptor, peroxisome proliferator-activated receptor (PPAR), have been studied in MPTP-induced PD and in the EAE model of multiple sclerosis. PPAR agonists were found to prevent neuroinflammation in EAE mice and to prevent the activation of MPTP to its toxic metabolites (30,31).…”