Comparison of PPAR Ligands as Modulators of Resolution of Inflammation, via Their Influence on Cytokines and Oxylipins Release in Astrocytes

Int J Mol Sci. 2020 Dec 16;21(24):9577. doi: 10.3390/ijms21249577.

Abstract

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 TNFα 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: PPARα (fenofibrate, GW6471); PPARβ (GW501516, GSK0660); PPARγ (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 PPARβ ligands possessed the strongest effect. The PPARβ 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, TNFα. The PPARβ agonist GW501516 and the PPARγ agonist, rosiglitazone induced the IL-10 release of the anti-inflammatory cytokine, IL-10; the cytokine index, (IL-10/TNFα) was more for GW501516. The PPARβ ligands, GW501516 and GSK0660, are also the strongest inhibitors of LPS-induced phosphorylation of p38, JNK, ERK MAPKs. Overall, our data revealed that the PPARβ ligands are a potential pro-resolution and anti-inflammatory drug for targeting glia-mediated neuroinflammation.

Keywords: GSK0660; GW501516; GW6471; GW9662; fenofibrate; peroxisome proliferator-activated receptors (PPAR); rosiglitazone; toll-like receptors (TLRs).

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fenofibrate / pharmacology
  • Interleukin-10 / metabolism*
  • Lipopolysaccharides / toxicity
  • MAP Kinase Kinase 4 / metabolism
  • Oxazoles / pharmacology
  • Oxylipins / metabolism*
  • PPAR gamma / agonists*
  • PPAR gamma / antagonists & inhibitors
  • PPAR-beta / agonists*
  • PPAR-beta / antagonists & inhibitors
  • Rats
  • Rats, Wistar
  • Rosiglitazone / pharmacology
  • Thiazoles / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tyrosine / analogs & derivatives
  • Tyrosine / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Anti-Inflammatory Agents
  • GW 501516
  • GW 6471
  • Lipopolysaccharides
  • Oxazoles
  • Oxylipins
  • PPAR gamma
  • PPAR-beta
  • Thiazoles
  • Tumor Necrosis Factor-alpha
  • Rosiglitazone
  • Interleukin-10
  • Tyrosine
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Fenofibrate