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Regulation of Glial Cell Functions by PPAR-gamma Natural and Synthetic Agonists.

Bernardo A, Minghetti L - PPAR Res (2008)

Bottom Line: In the recent years, the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), 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-gamma agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Delta(12,14) prostaglandin J(2)), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory 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-gamma 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy.

ABSTRACT
In the recent years, the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), 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-gamma agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Delta(12,14) prostaglandin J(2)), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory 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-gamma 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-gamma 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.

No MeSH data available.


Related in: MedlinePlus

PPAR-γ expression in culture rat oligodendrocytes and in white matter (postnatalday 19) in rat model of global perinatal asphyxia. (a) Immunocytochemistry of rat OL progenitor cultures, prepared as previouslydescribed [40] for PPAR-γ (upperpanel) and the OL marker O4 (lower panel). (b) Western blot analysis of whitematter homogenates from rats at postnatal day 19 subjected to 20 minutes ofperinatal asphyxia (hypoxic) and from controls, prepared as described inPiscopo et al. [48]. Inset show the decreased levels of MBP in hypoxicrats at pnd 19.
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fig2: PPAR-γ expression in culture rat oligodendrocytes and in white matter (postnatalday 19) in rat model of global perinatal asphyxia. (a) Immunocytochemistry of rat OL progenitor cultures, prepared as previouslydescribed [40] for PPAR-γ (upperpanel) and the OL marker O4 (lower panel). (b) Western blot analysis of whitematter homogenates from rats at postnatal day 19 subjected to 20 minutes ofperinatal asphyxia (hypoxic) and from controls, prepared as described inPiscopo et al. [48]. Inset show the decreased levels of MBP in hypoxicrats at pnd 19.

Mentions: Oligodendrocytes (OLs) are the myelin-forming cells of the CNS. Their differentiation fromprecursor to mature cells occurs through a series of stages that can be definedby morphological and antigenic changes occurring in vivo as well as in culturesystems [38]. During development and repair OLs extend elongated processes,forming multilamellar sheaths around neuronal axons. The formation, growth, andmaintenance of the myelin sheath are prominent parts of neural development andnervous system function. As for OL maturation, myelin formation is a multistepprocess, involving recruitment to germination sites, proliferation ofundifferentiated OL progenitors and their differentiation to mature OLs,producing myelin. Damage to OLs as a result of oxidative stress is considered akey pathogenetic pathway in several adult and infant human diseases. Asubstantial number of in vitro and in vivo studies has shown a maturation-dependentvulnerability to oxidative stress of the OL lineage [39–41], suggesting that OL progenitor is a key target forlimit white matter damage and promote myelin repair [42].Oligodendrocytes are major lipid producing cells, as required for myelinformation and maintenance. Given the role of PPARs in lipid metabolism it isconceivable that this group of nuclear receptor play a major role in OLdifferentiation and function. Although PPAR-β/δhas been long considered the PPAR type mainly expressed in OLs and involved inmyelination [43, 44], recent findings support an important role for PPAR-γactivators in OL protection and differentiation. The first evidence for a roleof PPAR-γ in OL differentiation was reported by Roth et al. [45].By using the B12, oligodendrocyte-like cell line and primary cultures of spinalcord OL precursors, the authors first demonstrated that these cells expressedall three PPAR isoforms and found that natural and synthetic PPAR-γagonists, but not other isoform activators, enhance process extension and cellmaturation. These effects were blocked by the PPAR-γ antagonist GW9662. The maturation of pre-OLswas accompanied by enhanced expression of alkyl-dihydroxyacetone phosphatesynthase (ADAPS), a peroxisomal enzyme required for the synthesis ofplasmalogen, an etherphospholipid essential for myelin formation. Theseobservations suggest that PPAR-γ mediated mechanisms may be important for OL differentiation and peroxisomefunctions. An important role for these organelles in maintaining OL and whitematter integrity has been recently demonstrated in mutant mice characterized bythe selective absence of functional peroxisomes from OLs [46]. Inline with the proposed role of PPAR-γ in controlling OL differentiation and functions, we have recently confirmed theexpression of PPAR-γ in highly purified rat OL cultures (Figure 2(a)). The level of expression isincreased with the OL maturation in vitro (Bernardo et al., in preparation). Inaddition, we found an increased expression of PPAR-γ in white matter of young rats (post natal day19) exposed to perinatal global asphyxia (Figure 2(b)). This model mimics someof the features of perinatal asphyxia, a major cause of immediate and delayedbrain damage in the newborn [47, 48], and is characterized by early oxidative stress,delayed behavioral deficits, and alteration in myelin formation, as indicatedby the strong reduction of myelin basic protein (MBP) expression (Figure 2(b)).Whether PPAR-γ over-expression is part of an adaptive response to the hypoxic condition aimedat restoring myelin formation or is part of an aberrant program leading behavioralimpairment remain to be established.


Regulation of Glial Cell Functions by PPAR-gamma Natural and Synthetic Agonists.

Bernardo A, Minghetti L - PPAR Res (2008)

PPAR-γ expression in culture rat oligodendrocytes and in white matter (postnatalday 19) in rat model of global perinatal asphyxia. (a) Immunocytochemistry of rat OL progenitor cultures, prepared as previouslydescribed [40] for PPAR-γ (upperpanel) and the OL marker O4 (lower panel). (b) Western blot analysis of whitematter homogenates from rats at postnatal day 19 subjected to 20 minutes ofperinatal asphyxia (hypoxic) and from controls, prepared as described inPiscopo et al. [48]. Inset show the decreased levels of MBP in hypoxicrats at pnd 19.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2367430&req=5

fig2: PPAR-γ expression in culture rat oligodendrocytes and in white matter (postnatalday 19) in rat model of global perinatal asphyxia. (a) Immunocytochemistry of rat OL progenitor cultures, prepared as previouslydescribed [40] for PPAR-γ (upperpanel) and the OL marker O4 (lower panel). (b) Western blot analysis of whitematter homogenates from rats at postnatal day 19 subjected to 20 minutes ofperinatal asphyxia (hypoxic) and from controls, prepared as described inPiscopo et al. [48]. Inset show the decreased levels of MBP in hypoxicrats at pnd 19.
Mentions: Oligodendrocytes (OLs) are the myelin-forming cells of the CNS. Their differentiation fromprecursor to mature cells occurs through a series of stages that can be definedby morphological and antigenic changes occurring in vivo as well as in culturesystems [38]. During development and repair OLs extend elongated processes,forming multilamellar sheaths around neuronal axons. The formation, growth, andmaintenance of the myelin sheath are prominent parts of neural development andnervous system function. As for OL maturation, myelin formation is a multistepprocess, involving recruitment to germination sites, proliferation ofundifferentiated OL progenitors and their differentiation to mature OLs,producing myelin. Damage to OLs as a result of oxidative stress is considered akey pathogenetic pathway in several adult and infant human diseases. Asubstantial number of in vitro and in vivo studies has shown a maturation-dependentvulnerability to oxidative stress of the OL lineage [39–41], suggesting that OL progenitor is a key target forlimit white matter damage and promote myelin repair [42].Oligodendrocytes are major lipid producing cells, as required for myelinformation and maintenance. Given the role of PPARs in lipid metabolism it isconceivable that this group of nuclear receptor play a major role in OLdifferentiation and function. Although PPAR-β/δhas been long considered the PPAR type mainly expressed in OLs and involved inmyelination [43, 44], recent findings support an important role for PPAR-γactivators in OL protection and differentiation. The first evidence for a roleof PPAR-γ in OL differentiation was reported by Roth et al. [45].By using the B12, oligodendrocyte-like cell line and primary cultures of spinalcord OL precursors, the authors first demonstrated that these cells expressedall three PPAR isoforms and found that natural and synthetic PPAR-γagonists, but not other isoform activators, enhance process extension and cellmaturation. These effects were blocked by the PPAR-γ antagonist GW9662. The maturation of pre-OLswas accompanied by enhanced expression of alkyl-dihydroxyacetone phosphatesynthase (ADAPS), a peroxisomal enzyme required for the synthesis ofplasmalogen, an etherphospholipid essential for myelin formation. Theseobservations suggest that PPAR-γ mediated mechanisms may be important for OL differentiation and peroxisomefunctions. An important role for these organelles in maintaining OL and whitematter integrity has been recently demonstrated in mutant mice characterized bythe selective absence of functional peroxisomes from OLs [46]. Inline with the proposed role of PPAR-γ in controlling OL differentiation and functions, we have recently confirmed theexpression of PPAR-γ in highly purified rat OL cultures (Figure 2(a)). The level of expression isincreased with the OL maturation in vitro (Bernardo et al., in preparation). Inaddition, we found an increased expression of PPAR-γ in white matter of young rats (post natal day19) exposed to perinatal global asphyxia (Figure 2(b)). This model mimics someof the features of perinatal asphyxia, a major cause of immediate and delayedbrain damage in the newborn [47, 48], and is characterized by early oxidative stress,delayed behavioral deficits, and alteration in myelin formation, as indicatedby the strong reduction of myelin basic protein (MBP) expression (Figure 2(b)).Whether PPAR-γ over-expression is part of an adaptive response to the hypoxic condition aimedat restoring myelin formation or is part of an aberrant program leading behavioralimpairment remain to be established.

Bottom Line: In the recent years, the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), 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-gamma agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Delta(12,14) prostaglandin J(2)), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory 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-gamma 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy.

ABSTRACT
In the recent years, the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), 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-gamma agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy Delta(12,14) prostaglandin J(2)), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory 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-gamma 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-gamma 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.

No MeSH data available.


Related in: MedlinePlus