Mechanisms of Peroxisome Proliferator Activated Receptor γ Regulation by Non-steroidal Anti-inflammatory Drugs

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation.

What makes gouty inflammation so variable?

“…The mechanisms of action of the primary treatment options for prophylaxis and treatment of acute gout clearly intersect with many of the novel inflammation-mediating pathways cited above. Specifically, indomethacin, ibuprofen, and certain other NSAIDs activate PPAR-γ [ 68 ].…”

Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics

“…However, a meta-analysis of 6 prospective epidemiologic studies did not show any significant advantage for the selective Aβ-42 lowering NSAIDs (SALAs) compared to the non-SALAs with regard to reducing risk of AD (Table 1) [36]. NSAIDs also have a variable effect on PPAR-gamma activation, ranging from minimal activation to strong partial agonist properties (such as ibuprofen, indomethacin, and naproxen) [27,28,140].…”

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

“…In several AD transgenic mouse models, levels of arachidonic acid, COX-2, and prostaglandins are elevated in the hippocampus [174,175]. Ibuprofen and indomethacin exert their effects by acting as agonists of peroxisome proliferatoractivated receptor-␥ (PPAR␥), while tarenflurbil (MPC-7869) and CHF5074 improve cognition and reduce brain inflammation [176][177][178]. Combination therapy of ibuprofen together with cromolyn (ALZT-OP1) targets the early stages of AD and ameliorates neuroinflammatory responses [165].…”