PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases

Abstract

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.

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

“…Diabetic patients face an increased propensity to suffer a stroke, and stroke inflicts significantly more damage in diabetic and hypertensive patients than in normoglycemic and/or normotensive individuals (32,33,101). It was first observed that the PPAR-alpha and the PPAR-gamma agonists protect against stroke and that this beneficial outcome is associated with improved endothelial relaxation, reduced oxidative stress and decreased VCAM1 and ICAM1 expression (26,101,104). Several animal studies have demonstrated the beneficial effects of TZDs in improving post-ischemic functional outcome.…”

T33, a novel peroxisome proliferator-activated receptor γ/α agonist, exerts neuroprotective action via its anti-inflammatory activities

“…The activation of PPARγ by T33 at the beginning of OGD did not lead to a higher level of activity of PPARγ after reperfusion, which could be attributed to mitigated stress by the treatment of T33. Moreover, previous studies have suggested that the activation of PPARγ promotes the repression of the exaggerated expression of inflammatory mediators that occurs in response to transient cerebral ischemia [12,38] . These actions of PPARγ could be mediated, at least in part, by inhibiting the I-κBα/NF-κB pathway, since I-κBα is a PPARγ target gene [39] .…”

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

“…Increased migration of Th2 lymphocytes across the BBB [79] and a possible role of Th2 mediators in neuroprotection and repair have recently been reported [80,81]. In addition to immunomodulatory activity of statins, lovastatin was also reported to induce the expression of PPAR-γ [82], whose activation is considered to be a pharmalogical target in neurodegenerative diseases [83]. These observations suggest that statin treatment may also provide neuroprotection by attenuation of inflammatory disease-induced glutamate/calcium-mediated demyelinative axonal damage in MS.…”