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, Parkinsons disease and Alzheimers disease.

Several lines of evidence suggest that peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists may control brain inflammation and, therefore, may be useful for the treatment of human CNS inflammatory conditions. The PPAR-γ agonists delay the onset and ameliorate clinical manifestations in animal demyelinating disease models, in which the beneficial effects are thought to be mainly related to anti-inflammatory effects on peripheral and brain immune cells. Direct effects on neurons, oligodendrocytes, and other CNS resident cells cannot be excluded, however. To analyze potential direct actions of PPAR-γ agonists on oligodendrocytes, we investigated the effects of both natural (15-deoxy Δ12,14 prostaglandin J2) and synthetic (pioglitazone) PPAR-γ agonists in primary cultures of rat oligodendrocyte progenitor cells. The PPAR-γ agonists promoted oligodendrocyte progenitor cell differentiation and enhanced their antioxidant defenses by increasing levels of catalase and copper-zinc superoxide dismutase while maintaining the overall homeostasis of the glutathione system. Protective effects were abolished in the presence of the specific PPAR-γ antagonist GW9662, indicating that they are specifically dependent on PPAR-γ. These observations suggest that in addition to their known anti-inflammatory effects, PPAR-γ agonists may protect oligodendrocyte progenitor cells by preserving their integrity and favoring their differentiation into myelin-forming cells. Thus, PPAR-γ may promote recovery from demyelination by direct effects on oligodendrocytes.

The term NSAID refers to structurally diverse chemical compounds that share the ability to inhibit the activity of the prostaglandin (PG) biosynthetic enzymes, the cyclooxygenase (COX) isoforms 1 and 2. The suppression of PG synthesis at sites of inflammation has been regarded as primarily responsible for the beneficial properties of NSAIDs, but several COX-independent effects have been described in recent years. Epidemiological studies indicate that NSAIDs are neuroprotective, although the mechanisms underlying their beneficial effect remain largely unknown. Microglial cells play a major role in brain inflammation and are often viewed as major contributors to the neurodegeneration. Therefore, microglia represent a likely target for NSAIDs within the brain. In the present review, we focused on the direct effects of NSAIDs and selective COX-2 inhibitors on microglial functions and discuss the potential efficacy in controlling brain inflammation.

The goal of our study was to assess whether the human immunodeficiency virus (HIV) coat protein gp120 induces functional alterations in astrocytes and microglia, known for their reactivity and involvement in most types of brain pathology. We hypothesized that gp120-induced anomalies in glial functions, if present, might be mediated by changes in the levels of intracellular messengers important for signal transduction, such as cAMP. Acute (10 min) exposure of cultured rat cortical astrocytes or microglia to 100 pM gp120 caused only a modest (50-60%), though statistically significant, elevation in cAMP levels, which was antagonized by the beta-adrenergic receptor antagonist propranolol. More importantly, the protein substantially depressed [by 30% (astrocytes) and 50% (microglia)] the large increase in cAMP induced by the beta-adrenergic agonist isoproterenol (10 nM), without affecting that induced by direct adenylate cyclase stimulation by forskolin. Qualitatively similar results were obtained using a glial fibrillary acidic protein (GFAP)-positive human glioma cell line. The depression of the beta-adrenergic response had functional consequences in both astrocytes and microglia. In astrocytes we studied the phosphorylation of the two major cytoskeletal proteins, vimentin and GFAP, which is normally stimulated by isoproterenol, and found that gp120 partially (40-50%) prevented such stimulation. In microglial cells, which are the major producers of inflammatory cytokines within the brain, gp120 partially antagonized the negative beta-adrenergic modulation of lipopolysaccharide (10 ng/ml)-induced production of tumor necrosis factor alpha. Our results suggest that, by interfering with the beta-adrenergic regulation of astrocytes and microglia, gp120 may alter astroglial "reactivity" and upset the delicate cytokine network responsible for the defense against viral and opportunistic infections.