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.