PPARγ, neuroinflammation, and disease
TL;DR: Observations suggest on the one hand a role for PPARγ-activating drugs in the treatment of chronic neuroinflammatory diseases-as shown for a patient with secondary progressive multiple sclerosis by Pershadsingh et al. and on the other hand a possible explanation for confusing and contradictory results in trials of nonsteroidal anti-inflammatory agents in Alzheimer's disease.
Abstract: Background
Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear transcription factors that are activated by fatty acids and their derivatives. One of these, PPARγ, regulates responsiveness to insulin in adipose cells, and PPARγ-activating drugs such as pioglitazone are used in the treatment of type 2 diabetes. PPARγ acts in myeloid-lineage cells, including T-cells and macrophages, to suppress their activation and their elaboration of inflammatory molecules. PPARγ activation also suppresses the activated phenotype in microglia, suggesting that PPARγ-activating drugs may be of benefit in chronic neuroinflammatory diseases. Some, but not all, nonsteroidal anti-inflammatory agents (indomethacin and ibuprofen in particular) also have activating effects on PPARγ.
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TL;DR: The multiple mechanisms of TZD-induced neuroprotection in various animal models of CNS injury with an emphasis on stroke are discussed.
Abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ2) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZD-induced neuroprotection in various animal models of CNS injury with an emphasis on stroke.
378 citations
TL;DR: Dysregulation of brain RAS plays a major role in aging-related changes and neurodegeneration by exacerbation of oxidative stress (OS) and neuroinflammation, which may be attenuated by pharmacological manipulation of RAS components.
Abstract: Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS) has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox) activation is a major regulator the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II, via its type 1 receptor (AT1), is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1-7/Mas receptor signaling. In addition, activation of renin-prorenin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization, such as estrogens, Rho kinase, insulin-like growth factor-1, tumor necrosis factor α, iron, peroxisome proliferator-activated receptor gamma, and toll-like receptors. Metabolic reprogramming has recently been involved in the regulation of the neuroinflammatory response. Interestingly, we have recently observed a mitochondrial RAS, which is altered in aged brains. In conclusion, dysregulation of brain RAS plays a major role in aging-related changes and neurodegeneration by exacerbation of oxidative stress and neuroinflammation, which may be attenuated by pharmacological manipulation of RAS components
162 citations
Cites background from "PPARγ, neuroinflammation, and disea..."
...PPAR-γ receptors are also involved in regulation of microglial activation and suppression of the proinflammatory phenotype (Bernardo et al., 2000; Mrak and Landreth, 2004)....
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TL;DR: A novel natural anti-oxidant extracted from the Chinese plant Hopea hainanensis, malibatol A (MA), decreased the infarct size and alleviated the brain injury after mice middle cerebral artery occlusion (MCAO).
Abstract: Activation of microglia plays a crucial role in immune and inflammatory processes after ischemic stroke. Microglia is reported with two opposing activated phenotypes, namely, classic phenotype (M1) and the alternative phenotype (M2). Inhibiting M1 while stimulating M2 has been suggested as a potential therapeutic approach in the treatment of stroke. In this study, we indicated that a novel natural anti-oxidant extracted from the Chinese plant Hopea hainanensis, malibatol A (MA), decreased the infarct size and alleviated the brain injury after mice middle cerebral artery occlusion (MCAO). MA inhibited expression inflammatory cytokines in not only MCAO mice but also lipopolysaccharide (LPS)-stimulated microglia. Moreover, treatment of MA decreased M1 markers (CD16, CD32, and CD86) and increased M2 markers (CD206, YM-1) while promoting the activation of nuclear receptor PPARγ. MA has anti-inflammatory effects in MCAO mice in a PPARγ-dependent manner, making it a potential candidate for stroke treatment.
157 citations
TL;DR: It is found that VCE-003 ameliorated the symptoms associated to TMEV infection, decreased microglia reactivity and modulated the expression of genes involved in MS pathophysiology, leading us to consider V CE-003 to have high potential for drug development against MS and perhaps other neuroinflammatory diseases.
Abstract: Phytocannabinoids like ∆(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) show a beneficial effect on neuroinflammatory and neurodegenerative processes through cell membrane cannabinoid receptor (CBr)-dependent and -independent mechanisms. Natural and synthetic cannabinoids also target the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ), an attractive molecular target for the treatment of neuroinflammation. As part of a study on the SAR of phytocannabinoids, we have investigated the effect of the oxidation modification in the resorcinol moiety of cannabigerol (CBG) on CB(1), CB(2) and PPARγ binding affinities, identifying cannabigerol quinone (VCE-003) as a potent anti-inflammatory agent. VCE-003 protected neuronal cells from excitotoxicity, activated PPARγ transcriptional activity and inhibited the release of pro-inflammatory mediators in LPS-stimulated microglial cells. Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis (MS) was used to investigate the anti-inflammatory activity of this compound in vivo. Motor function performance was evaluated and the neuroinflammatory response and gene expression pattern in brain and spinal cord were studied by immunostaining and qRT-PCR. We found that VCE-003 ameliorated the symptoms associated to TMEV infection, decreased microglia reactivity and modulated the expression of genes involved in MS pathophysiology. These data lead us to consider VCE-003 to have high potential for drug development against MS and perhaps other neuroinflammatory diseases.
110 citations
Cites background from "PPARγ, neuroinflammation, and disea..."
...Interestingly, PPARγ has been detected in neurons and glial cells (Moreno et al. 2004) and participates in mechanisms that control activation of microglia (Mrak and Landreth 2004)....
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TL;DR: The focus is on Alzheimer’s disease, but the concepts are transferrable to other neurodegenerative disorders with an inflammatory component, as well as development of novel synthetic compounds that selectively downregulate neuroinflammatory responses.
Abstract: The increased appreciation of the importance of glial cell-propagated inflammation (termed ‘neuroinflammation’) in the progression of pathophysiology for diverse neurodegenerative diseases, has hei...
103 citations
Cites background from "PPARγ, neuroinflammation, and disea..."
...Based on these preclinical and clinical observations, the efficacy of the PPARγ agonist pioglitazone is currently being tested in a Phase II clinical trial of mild/moderate AD [50]....
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References
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TL;DR: It is shown that PPAR-γ is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPar-γ ligands, suggesting that PPARS and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses.
Abstract: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen PPAR-gamma has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates Naturally occurring compounds such as fatty acids and the prostaglandin D2 metabolite 15-deoxy-delta prostaglandin J2 (15d-PGJ2) bind to PPAR-gamma and stimulate transcription of target genes Prostaglandin D2 metabolites have not yet been identified in adipose tissue, but are major products of arachidonic-acid metabolism in macrophages, raising the possibility that they might serve as endogenous PPAR-gamma ligands in this cell type Here we show that PPAR-gamma is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPAR-gamma ligands PPAR-gamma inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-kappaB These observations suggest that PPAR-gamma and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR-gamma ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects
3,587 citations
"PPARγ, neuroinflammation, and disea..." refers background in this paper
...PPARγ-activating drugs were subsequently found to regulate T-cell responsiveness [7,8] and to suppress macrophage and microglia activation [9-11]....
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TL;DR: A member of the steroid hormone receptor superfamily of ligand-activated transcription factors is cloned that is activated by a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.
Abstract: We have cloned a member of the steroid hormone receptor superfamily of ligand-activated transcription factors. The receptor homologue is activated by a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes. Identification of a peroxisome proliferator-activated receptor should help elucidate the mechanism of the hypolipidaemic effect of these hepatocarcinogens and aid evaluation of their potential carcinogenic risk to man.
3,370 citations
"PPARγ, neuroinflammation, and disea..." refers background in this paper
...By the 1990s, when PPARs were identified and shown to be transcription factors [5], interest had waned in cancer circles....
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TL;DR: Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).
Abstract: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor family of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and repression Expression of PPAR-gamma is an early and pivotal event in the differentiation of adipocytes Several agents that promote differentiation of fibroblast lines into adipocytes have been shown to be PPAR-gamma agonists, including several prostanoids, of which 15-deoxy-delta-prostaglandin J2 is the most potent, as well as members of a new class of oral antidiabetic agents, the thiazolidinediones, and a variety of non-steroidal anti-inflammatory drugs (NSAIDs) Here we show that PPAR-gamma agonists suppress monocyte elaboration of inflammatory cytokines at agonist concentrations similar to those found to be effective for the promotion of adipogenesis Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase)
2,866 citations
TL;DR: A new gene is described, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways and encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway.
Abstract: Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development1,2. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci)3,4, whereas Wg signal transduction causes increased stability of Armadillo (Arm/β-catenin)5, a possible co-factor for thetranscriptional regulator Lef1/TCF6. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh− and Wg− responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway7,8,9. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasomepathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.
1,778 citations
1,540 citations
"PPARγ, neuroinflammation, and disea..." refers background in this paper
...Christian de Duve, in Brussels, Belgium, subsequently isolated these structures, demonstrated hydrogen peroxide generation, and renamed them peroxisomes [3]....
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