PPARs: a new target for neuroprotection
- R Bordet1,
- P Gelé1,
- P Duriez2,
- J-C Fruchart2
- 1Département de Pharmacologie, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université de Lille 2, Lille, France
- 2Département d’Athérosclérose, Institut de Médecine Prédictive et de Recherche Thérapeutique, Université de Lille 2, Lille, France
- Correspondence to: R Bordet EA1046 – Département de Pharmacologie, Faculté de Médecine, 1 place de Verdun, 59045 Lille Cedex, France; bordet{at}univ-lille2.fr
PPAR agonists are potential neuroprotective drugs
Peroxisome proliferators-activated receptors (PPARs) are ligand activated transcription factors belonging to the nuclear receptor superfamily.1 Three isoforms of PPARs (α, β/δ, and γ) have been identified and display distinct physiological and pharmacological functions depending on their target genes and their tissue distribution.2,3 Indeed, the activation of PPARα, both by natural ligands such as fatty acids and eicosanoid derivates or by synthetic ligands (lipid lowering fibrates), regulates lipid and lipoprotein metabolism.4 Activation of PPARγ by prostaglandins or by synthetic ligands, such as anti-diabetic thiazolidinediones, regulates glucose metabolism by modulating insulin sensitivity.4 Non-steroidal anti-inflammatory drugs are also weak agonists of PPARγ and PPARα. PPARβ/δ is one of the most widely expressed members of the PPAR family. Until recently, the function of PPARβ/δ remained elusive but recent data have shown that PPARβ/δ also plays a key role in lipid metabolism, as it regulates serum lipid profiles and fatty acid β-oxidation in muscle and adipose tissue. Synthetic ligands of PPARβ/δ are currently in preclinical phases of development.5
INFLAMMATORY PATHWAYS
In addition to affecting metabolic pathways, PPARs are also able to regulate inflammatory pathways by transrepression of transcription factors (NFκB) and to regulate oxidative pathways.1 PPARα activation induces expression and activation of anti-oxidant enzymes such as superoxide dismutase or glutathione peroxidase. As regards inflammatory pathways, PPARα activation prevents the synthesis and release of cytokines (interleukin 6, tumour necrosis factor α) or the induction of some inflammatory mediators such as cyclooxygenase-2 or adhesion proteins. PPARγ activation also reduces the expression of inducible nitric oxide synthase and cyclooxygenase-2 as well as the production of proinflammatory cytokines. These mechanisms explain how activation of PPARs by synthetic ligands reduces inflammation in different tissues and different animal models of inflammatory diseases (vascular inflammation of atherosclerosis, inflammatory bowel disease, arthritis, …
