Authors: Bernardo, Antonietta; Minghetti, Luisa

Source: Current Pharmaceutical Design, Volume 12, Number 1, January 2006 , pp. 93-109(17)

Publisher: Bentham Science Publishers

Abstract:

The peroxisome proliferator-activated receptor-g (PPAR-γ) 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-γ is involved in the regulation of macrophage differentiation and activation in the peripheral organs has prompted the investigation of the functional role of PPAR-γ in microglial cells, the main macrophage population of the CNS. The present review summarizes the several lines of evidence supporting that PPAR-γ 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-γ agonist, 15d-prostaglandin J2 may contribute to the safe elimination of activated microglia by inducing apoptosis. Synthetic PPAR- g agonists do not entirely reproduce the range of 15d-prostaglandin J2 effects, suggesting that PPAR-γ independent mechanisms are also involved in the action of this prostaglandin. In addition to microglia, PPAR-γ 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-γ agonists in human brain diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease.

Keywords: CNS; inflammation; microglial activation; neurodegenerations; NSAIDs; PPAR-γ; 15d-PGJ2; TZDs

Document Type: Research article

Affiliations: 1: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy;

Publication date: 2006-01-01

More about this publication?

• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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