PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases.
PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors belonging to the so-called nuclear receptor family. The three isoforms of PPAR (alpha, beta/delta and gamma) are involved in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARalpha and PPARgamma activation also induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain why PPARalpha or PPARgamma activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates and other non-fibrate PPARalpha activators as well as thiazolidinediones and other non-thiazolidinedione PPARgamma agonists have been demonstrated to induce both preventive and acute neuroprotection. This neuroprotective effect involves both cerebral and vascular mechanisms. PPAR activation induces a decrease in neuronal death by prevention of oxidative or inflammatory mechanisms implicated in cerebral injury. PPARalpha activation induces also a vascular protection as demonstrated by prevention of post-ischaemic endothelial dysfunction. These vascular effects result from a decrease in oxidative stress and prevention of adhesion proteins, such as vascular cell adhesion molecule 1 or intercellular cell-adhesion molecule 1. Moreover, PPAR activation might be able to induce neurorepair and endothelium regeneration. Beyond neuroprotection in cerebral ischaemia, PPARs are also pertinent pharmacological targets to induce neuroprotection in chronic neurodegenerative diseases.
Bordet
R
R
EA1046 Department of Medical Pharmacology, Faculty of Medicine, Institute of Predictive Medicine and Therapeutic Research, University Lille 2 and Lille University Hospital, 1 place de Verdun, 59045 Lille Cedex, France. email bordet@univ-lille2.fr
Ouk
T
T
Petrault
O
O
Gelé
P
P
Gautier
S
S
Laprais
M
M
Deplanque
D
D
Duriez
P
P
Staels
B
B
Fruchart
J C
JC
Bastide
M
M
D001921:Brain / Q000166:cytology / Q000473:pathology / Q000502:physiology; D001930:Brain Injuries / Q000188:drug therapy; D002545:Brain Ischemia / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects*; D006801:Humans; D008959:Models, Neurological; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D009474:Neurons / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D047492:Peroxisome Proliferator-Activated Receptors / Q000187:drug effects / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000188:drug therapy; D020521:Stroke / Q000188:drug therapy*; D009435:Synaptic Transmission
D018696:Neuroprotective Agents; D047492:Peroxisome Proliferator-Activated Receptors