[Frontiers in Bioscience 13, 1813-1826, January 1, 2008]

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

Ramya Kapadia, Jae-Hyuk Yi, Raghu Vemuganti

Department of Neurological Surgery and the Neuroscience Training Program, University of Wisconsin, Madison WI 53792

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Inflammation in stroke
2.2. Role of transcription factors in post-ischemic inflammation
2.3. Peroxisome proliferator-activated receptor-gamma
2.3.1. PPAR-gamma ligand-binding and target gene transcription
2.3.2. Metabolic and anti-inflammatory effects of PPAR-gamma
2.3.3. Anti-inflammatory effects of PPAR-gamma activation by TZDs
2.3.4. Anti-inflammatory effects of PPAR-gamma activation: contrasting evidence
3. PPAR-gamma effects in the CNS
4. PPAR-gamma ligands induce neuroprotection after spinal cord injury
5. PPAR-gamma and focal cerebral ischemia
5.1. Pre-treatment with PPAR-gamma agonists induces neuroprotection after cerebral ischemia
5.2. TZDs prevent ischemic cell death by decreasing oxidative stress and ROS production
5.3. Ligand efficacy of PPAR agonists, rosiglitazone and pioglitazone in CNS injury
6. PPAR-gamma-independent-mechanisms
7. PPAR-alpha and PPAR-delta/beta agonist-induced neuroprotection
8. Conclusions
9. Acknowledgements
10. References

1. ABSTRACT

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ2) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZD-induced neuroprotection in various animal models of CNS injury with an emphasis on stroke.