Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 24, Pages -Publisher
MDPI
DOI: 10.3390/ijms21249577
Keywords
peroxisome proliferator-activated receptors (PPAR); rosiglitazone; GW9662; fenofibrate; GW6471; GW501516; GSK0660; toll-like receptors (TLRs)
Funding
- Russian Science Foundation [16-15-10298]
- Russian Science Foundation [16-15-10298] Funding Source: Russian Science Foundation
Ask authors/readers for more resources
Neuroinflammation is a key process of many neurodegenerative diseases and other brain disturbances, and astrocytes play an essential role in neuroinflammation. Therefore, the regulation of astrocyte responses for inflammatory stimuli, using small molecules, is a potential therapeutic strategy. We investigated the potency of peroxisome proliferator-activated receptor (PPAR) ligands to modulate the stimulating effect of lipopolysaccharide (LPS) in the primary rat astrocytes on (1) polyunsaturated fatty acid (PUFAs) derivative (oxylipins) synthesis; (2) cytokines TNF alpha and interleukin-10 (IL-10) release; (3) p38, JNK, ERK mitogen-activated protein kinase (MAPKs) phosphorylation. Astrocytes were exposed to LPS alone or in combination with the PPAR ligands: PPAR alpha (fenofibrate, GW6471); PPAR beta (GW501516, GSK0660); PPAR gamma (rosiglitazone, GW9662). We detected 28 oxylipins with mass spectrometry (UPLC-MS/MS), classified according to their metabolic pathways: cyclooxygenase (COX), cytochrome P450 monooxygenases (CYP), lipoxygenase (LOX) and PUFAs: arachidonic (AA), docosahexaenoic (DHA), eicosapentaenoic (EPA). All tested PPAR ligands decrease COX-derived oxylipins; both PPAR beta ligands possessed the strongest effect. The PPAR beta agonist, GW501516 is a strong inducer of pro-resolution substances, derivatives of DHA: 4-HDoHE, 11-HDoHE, 17-HDoHE. All tested PPAR ligands decreased the release of the proinflammatory cytokine, TNF alpha. The PPAR beta agonist GW501516 and the PPAR gamma agonist, rosiglitazone induced the IL-10 release of the anti-inflammatory cytokine, IL-10; the cytokine index, (IL-10/TNF alpha) was more for GW501516. The PPAR beta ligands, GW501516 and GSK0660, are also the strongest inhibitors of LPS-induced phosphorylation of p38, JNK, ERK MAPKs. Overall, our data revealed that the PPAR beta ligands are a potential pro-resolution and anti-inflammatory drug for targeting glia-mediated neuroinflammation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available