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In the recent years, the peroxisome proliferator-activated receptor-γ (PPAR-γ), a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR-γ agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Δ12,14 prostaglandin J2), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal antiinflammatory drugs) have shown anti-inflammatory and protective effects in several experimental models of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR-γ agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes), as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR-γ agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation. [ABSTRACT FROM AUTHOR]

The last decade has witnessed an increasing interest for the role played by the peroxisome proliferator-activated receptor-γ (PPAR-γ) in controlling inflammation in peripheral organs as well as in the brain. Activation of PPAR-γ has been shown to control the response of microglial cells, the main macrophage population found in brain parenchyma, and limit the inflammation. The anti-inflammatory capacity of PPAR-γ agonists has led to the hypothesis that PPAR-γ might be targeted to modulate degenerative brain diseases in which inflammation has been increasingly recognized as a significant component. Recent experimental evidence suggests that PPAR-γ agonists could be exploited to treat ocular diseases such as diabetic retinopathy, age-related macular degeneration, autoimmune uveitis, and optic neuritis where inflammation has relevant role. Additional PPAR-γ agonist beneficial effects could involve amelioration of retinal microcirculation and inhibition of neovascularization. However, PPAR-γ activation could, in some instances, aggravate the ocular pathology, for example, by increasing the synthesis of vascular endothelial growth factor, a proangiogenic factor that could trigger a vicious circle and further deteriorate retinal perfusion. The development of new in vivo and in vitro models to study ocular inflammation and how to modulate for the eye benefit will be instrumental for the search of effective therapies. [ABSTRACT FROM AUTHOR]

We have previously reported that rat primary microglial cultures express the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) and that several functions associated with the activation of these cells, including nitric oxide (NO) and tumor necrosis factor-α synthesis, are down-regulated by 15-deoxy-Δ12,14 -prostaglandin J2 (15d-PGJ2 ) and ciglitazone, two specific PPAR-γ agonists. Here we demonstrate that microglial cells not only express a functionally active PPAR-γ, but also synthesize large amounts of 15d-PGJ2 upon stimulation with lipopolysaccharide (LPS). In addition, we show that, although 15d-PGJ2 and ciglitazone were equally effective in reducing microglial activation when used at 1–5 µ m concentrations, 15d-PGJ2 , but not of ciglitazone, reduced PGE2 production at low concentration (0.1 µ m ) and induced a time-dependent microglial impairment and apoptosis at high concentration (10 µ m ). Interestingly, the inhibition of PGE2 production was achieved mainly through the inhibition of cycloxygenase-2 enzymatic activity, as the expression of this enzyme and that of the microsomal isoform of PGE synthase remained unaltered. These findings suggest that 15d-PGJ2 affects the functional state and the survival of activated microglia through mechanisms only in part dependent on PPAR-γ and that the concentration of 15d-PGJ2 is crucial in determining the particular microglial function affected. [ABSTRACT FROM AUTHOR]

AbstractThe peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of a large group of nuclear receptors controlling the proliferation of peroxisomes that is involved in the downregulation of macrophage functions. Here, we report that PPAR-γ was constitutively expressed in rat primary microglial cultures and that such expression was downregulated during microglial activation by endotoxin (LPS). The presence of the PPAR-γ natural ligand 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) counteracted the repression of PPAR-γ expression caused by LPS. In microglial cultures stimulated by LPS, interferon-γ (IFN-γ) or by their combination, 15d-PGJ2 reduced the production of nitric oxide (NO) and the expression of inducible NO synthase (iNOS). The inhibitory effect was dose-dependent and did not involve an elevation of cyclic AMP, a second messenger known to inhibit NOS expression in microglia. In addition, 15d-PGJ2 down-regulated other microglial functions, such as tumour necrosis factor-α (TNF-α) synthesis and major histocompatibility complex class II (MHC class II) expression. The effects of 15d-PGJ2 occurred, at least in part, through the repression of two important transcription factors, the signal transducer and activator of transcription 1 and the nuclear factor κB, known to mediate IFN-γ and LPS cell signalling. Our observations suggest that 15d-PGJ2, the synthesis of which is likely to occur within the brain, could play an important role in preventing brain damage associated with excessive microglial activation. [ABSTRACT FROM AUTHOR]

Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigen-presenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/β plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1β play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3+CD25- regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8+ T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses. [ABSTRACT FROM AUTHOR]

The myelin sheath wraps around axons, allowing saltatory currents to be transmitted along neurons. Several genetic, viral, or environmental factors can damage the central nervous system (CNS) myelin sheath during life. Unless the myelin sheath is repaired, these insults will lead to neurodegeneration. Remyelination occurs spontaneously upon myelin injury in healthy individuals but can fail in several demyelination pathologies or as a consequence of aging. Thus, pharmacological intervention that promotes CNS remyelination could have a major impact on patient's lives by delaying or even preventing neurodegeneration. Drugs promoting CNS remyelination in animal models have been identified recently, mostly as a result of repurposing phenotypical screening campaigns that used novel oligodendrocyte cellular models. Although none of these have as yet arrived in the clinic, promising candidates are on the way. Many questions remain. Among the most relevant is the question if there is a time window when remyelination drugs should be administrated and why adult remyelination fails in many neurodegenerative pathologies. Moreover, a significant challenge in the field is how to reconstitute the oligodendrocyte/axon interaction environment representative of healthy as well as disease microenvironments in drug screening campaigns, so that drugs can be screened in the most appropriate disease-relevant conditions. Here we will provide an overview of how the field of in vitro models developed over recent years and recent biological findings about how oligodendrocytes mature after reactivation of their staminal niche. These data have posed novel questions and opened new views about how the adult brain is repaired after myelin injury and we will discuss how these new findings might change future drug screening campaigns for CNS regenerative drugs. [ABSTRACT FROM AUTHOR]

Niemann-Pick type C1 (NPC1) disease is a rare neurovisceral disorder characterized by intracellular accumulation of unesterified cholesterol, sphingolipids, and other lipids in the lysosomal compartment. A deregulation of lysosomal calcium has been identified as one of the earliest steps of the degenerative process. Since adenosine A2A receptors (A2ARs) control lysosome trafficking and pH, which closely regulates lysosomal calcium, we hypothesized a role for these receptors in NPC1. The aim of this study was to evaluate the effects of the A2AR agonist CGS21680 on human control and NPC1 fibroblasts. We show that CGS21680 raises lysosomal calcium levels and rescues mitochondrial functionality (mitochondrial inner membrane potential and expression of the complex IV of the mitochondrial respiratory chain), which is compromised in NPC1 cells. These effects are prevented by the selective blockade of A2ARs by the antagonist ZM241385. The effects of A2AR activation on lysosomal calcium are not mediated by the cAMP/PKA pathway but they appear to involve the phosphorylation of ERK1/2. Finally, CGS21680 reduces cholesterol accumulation (Filipin III staining), which is the main criterion currently used for identification of a compound or pathway that would be beneficial for NPC disease, and such an effect is prevented by the Ca(2+) chelator BAPTA-AM. Our findings strongly support the hypothesis that A2AR agonists may represent a therapeutic option for NPC1 and provide insights on their mechanisms of action.

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.

We have previously reported that rat primary microglial cultures express the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and that several functions associated with the activation of these cells, including nitric oxide (NO) and tumor necrosis factor-alpha synthesis, are down-regulated by 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, two specific PPAR-gamma agonists. Here we demonstrate that microglial cells not only express a functionally active PPAR-gamma, but also synthesize large amounts of 15d-PGJ2 upon stimulation with lipopolysaccharide (LPS). In addition, we show that, although 15d-PGJ2 and ciglitazone were equally effective in reducing microglial activation when used at 1-5 microm concentrations, 15d-PGJ2, but not of ciglitazone, reduced PGE2 production at low concentration (0.1 microm) and induced a time-dependent microglial impairment and apoptosis at high concentration (10 microm). Interestingly, the inhibition of PGE2 production was achieved mainly through the inhibition of cycloxygenase-2 enzymatic activity, as the expression of this enzyme and that of the microsomal isoform of PGE synthase remained unaltered. These findings suggest that 15d-PGJ2 affects the functional state and the survival of activated microglia through mechanisms only in part dependent on PPAR-gamma and that the concentration of 15d-PGJ2 is crucial in determining the particular microglial function affected.

To understand the basis of oligodendrocyte (OL) susceptibility to oxidative injury, purified rat OL cultures at different stages of maturation were exposed to nitric oxide (NO) donors with fast or slow kinetics of release and to tert-butyl-hydroperoxide, a membrane-permeant organic hydroperoxide. OL precursors (pre-OL) displayed the highest vulnerability to both oxygen or nitrogen reactive species, whereas mature OLs were uniquely vulnerable to long-lasting levels of NO. Cell death occurred by necrosis as well as apoptosis associated with increased caspase-3 activity and, only in the case of pre-OLs, with a decreased expression of the anti-apoptotic protein bcl-2. Pre-OLs were also more susceptible than mature OLs to lipid peroxidation, as measured by F2-isoprostane content in culture media. Finally, pre-OLs, but not mature OLs, expressed high levels of the mitochondrial scavenging enzyme Mn superoxide dismutase, suggesting that pre-OLs may efficiently convert anion superoxide into hydrogen peroxide and, paradoxically, be more predisposed than mature OLs to a toxic imbalance between hydrogen peroxide production and detoxification processes. These data suggest that susceptibility to lipid peroxidation, expression of the scavenging enzyme Mn superoxide dismutase and of the anti-apoptotic protein bcl-2, may contribute to the maturation-dependent vulnerability of OLs to oxidant injury.