PPAR-γ Agonists as Regulators of Microglial Activation and Brain Inflammation

Abstract

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) belongs to a large group of nuclear receptors controlling reproduction, metabolism, development and immune response. Upon activation by specific agonists, these receptors form dimers and translocate to the nucleus, where they act as agonist-dependent transcription factors and regulate gene expression by binding to specific promoter regions of target genes. The observation that PPAR-gamma is involved in the regulation of macrophage differentiation and activation in the peripheral organs has prompted the investigation of the functional role of PPAR-gamma in microglial cells, the main macrophage population of the CNS. The present review summarizes the several lines of evidence supporting that PPAR-gamma natural and synthetic agonists may control brain inflammation by inhibiting several functions associated to microglial activation, such as the expression of surface antigens and the synthesis of nitric oxide, prostaglandins, inflammatory cytokines and chemokines. Moreover, one of the major natural PPAR-gamma agonist, 15d-prostaglandin J(2) may contribute to the safe elimination of activated microglia by inducing apoptosis. Synthetic PPAR-gamma agonists do not entirely reproduce the range of 15d-prostaglandin J(2) effects, suggesting that PPAR-gamma independent mechanisms are also involved in the action of this prostaglandin. In addition to microglia, PPAR-gamma agonists affect functions and survival of other neural cells, including astrocytes, oligodendrocytes and neurons. Although most of the evidence comes from in vitro observations, an increasing number of studies in animal models further supports the potential therapeutic use of PPAR-gamma agonists in human brain diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease.

Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

“…PPAR-γ is one of three different PPAR isoforms that regulates gene expression using various ligand-dependent and -independent molecular processes to decrease several pro-inflammatory genes and immunoregulate microglia [5,8,11]. However, its expression was not determined in our intrastriatal LPS model [22].…”

CITED2 Signals through Peroxisome Proliferator-Activated Receptor-γ to Regulate Death of Cortical Neurons after DNA Damage

“…The role of PPAR␥ likely depends on the context of the cell or model system. For example, PPAR␥ is known to regulate neuroinflammation by inhibiting microglial activation (Bernardo and Minghetti, 2006). In this context, PPAR␥ activation strategies would be expected to promote survival under contexts in which inflammation is a critical component of injury.…”

Peroxisome Proliferator-activated Receptor γ Up-regulates the Bcl-2 Anti-apoptotic Protein in Neurons and Induces Mitochondrial Stabilization and Protection against Oxidative Stress and Apoptosis

“…TZDs have been proposed as potential therapeutic agents for both Alzheimer disease and multiple sclerosis (4). Most of the neuroprotective effects of TZDs are ascribed to either improved insulin sensitivity or to their anti-inflammatory action through PPAR␥ activation in glial cells (5)(6)(7). However, activation of PPAR␥ by three different TZDs protects rat hippocampal neurons against ␤-amyloid (A␤)-induced damage (8), and the TZD rosiglitazone (RGZ) protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity (9).…”