Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia

<p<Abstract</p< <p<Background</p< <p<Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p< Ausführliche Beschreibung

Gespeichert in:

Autor*in:	de Oliveira Antonio CP [verfasserIn] Candelario-Jalil Eduardo [verfasserIn] Langbein Julia [verfasserIn] Wendeburg Lena [verfasserIn] Bhatia Harsharan S [verfasserIn] Schlachetzki Johannes CM [verfasserIn] Biber Knut [verfasserIn] Fiebich Bernd L [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2012

Schlagwörter:	microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins

Übergeordnetes Werk:	In: Journal of Neuroinflammation - BMC, 2004, 9(2012), 1, p 2
Übergeordnetes Werk:	volume:9 ; year:2012 ; number:1, p 2

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/1742-2094-9-2

Katalog-ID:	DOAJ032769865

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author_variant	d o a c doac c j e cje l j lj w l wl b h s bhs s j c sjc b k bk f b l fbl
matchkey_str	article:17422094:2012----::hraooiaihbtooatndwsraptwymdltshepesoocxa
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allfields	10.1186/1742-2094-9-2 doi (DE-627)DOAJ032769865 (DE-599)DOAJb6c84376d15441689031a6dac0e491e0 DE-627 ger DE-627 rakwb eng RC346-429 de Oliveira Antonio CP verfasserin aut Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p< microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins Neurology. Diseases of the nervous system Candelario-Jalil Eduardo verfasserin aut Langbein Julia verfasserin aut Wendeburg Lena verfasserin aut Bhatia Harsharan S verfasserin aut Schlachetzki Johannes CM verfasserin aut Biber Knut verfasserin aut Fiebich Bernd L verfasserin aut In Journal of Neuroinflammation BMC, 2004 9(2012), 1, p 2 (DE-627)391784781 (DE-600)2156455-3 17422094 nnns volume:9 year:2012 number:1, p 2 https://doi.org/10.1186/1742-2094-9-2 kostenfrei https://doaj.org/article/b6c84376d15441689031a6dac0e491e0 kostenfrei http://www.jneuroinflammation.com/content/9/1/2 kostenfrei https://doaj.org/toc/1742-2094 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2012 1, p 2
spelling	10.1186/1742-2094-9-2 doi (DE-627)DOAJ032769865 (DE-599)DOAJb6c84376d15441689031a6dac0e491e0 DE-627 ger DE-627 rakwb eng RC346-429 de Oliveira Antonio CP verfasserin aut Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p< microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins Neurology. Diseases of the nervous system Candelario-Jalil Eduardo verfasserin aut Langbein Julia verfasserin aut Wendeburg Lena verfasserin aut Bhatia Harsharan S verfasserin aut Schlachetzki Johannes CM verfasserin aut Biber Knut verfasserin aut Fiebich Bernd L verfasserin aut In Journal of Neuroinflammation BMC, 2004 9(2012), 1, p 2 (DE-627)391784781 (DE-600)2156455-3 17422094 nnns volume:9 year:2012 number:1, p 2 https://doi.org/10.1186/1742-2094-9-2 kostenfrei https://doaj.org/article/b6c84376d15441689031a6dac0e491e0 kostenfrei http://www.jneuroinflammation.com/content/9/1/2 kostenfrei https://doaj.org/toc/1742-2094 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2012 1, p 2
allfields_unstemmed	10.1186/1742-2094-9-2 doi (DE-627)DOAJ032769865 (DE-599)DOAJb6c84376d15441689031a6dac0e491e0 DE-627 ger DE-627 rakwb eng RC346-429 de Oliveira Antonio CP verfasserin aut Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p< microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins Neurology. Diseases of the nervous system Candelario-Jalil Eduardo verfasserin aut Langbein Julia verfasserin aut Wendeburg Lena verfasserin aut Bhatia Harsharan S verfasserin aut Schlachetzki Johannes CM verfasserin aut Biber Knut verfasserin aut Fiebich Bernd L verfasserin aut In Journal of Neuroinflammation BMC, 2004 9(2012), 1, p 2 (DE-627)391784781 (DE-600)2156455-3 17422094 nnns volume:9 year:2012 number:1, p 2 https://doi.org/10.1186/1742-2094-9-2 kostenfrei https://doaj.org/article/b6c84376d15441689031a6dac0e491e0 kostenfrei http://www.jneuroinflammation.com/content/9/1/2 kostenfrei https://doaj.org/toc/1742-2094 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2012 1, p 2
allfieldsGer	10.1186/1742-2094-9-2 doi (DE-627)DOAJ032769865 (DE-599)DOAJb6c84376d15441689031a6dac0e491e0 DE-627 ger DE-627 rakwb eng RC346-429 de Oliveira Antonio CP verfasserin aut Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p< microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins Neurology. Diseases of the nervous system Candelario-Jalil Eduardo verfasserin aut Langbein Julia verfasserin aut Wendeburg Lena verfasserin aut Bhatia Harsharan S verfasserin aut Schlachetzki Johannes CM verfasserin aut Biber Knut verfasserin aut Fiebich Bernd L verfasserin aut In Journal of Neuroinflammation BMC, 2004 9(2012), 1, p 2 (DE-627)391784781 (DE-600)2156455-3 17422094 nnns volume:9 year:2012 number:1, p 2 https://doi.org/10.1186/1742-2094-9-2 kostenfrei https://doaj.org/article/b6c84376d15441689031a6dac0e491e0 kostenfrei http://www.jneuroinflammation.com/content/9/1/2 kostenfrei https://doaj.org/toc/1742-2094 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2012 1, p 2
allfieldsSound	10.1186/1742-2094-9-2 doi (DE-627)DOAJ032769865 (DE-599)DOAJb6c84376d15441689031a6dac0e491e0 DE-627 ger DE-627 rakwb eng RC346-429 de Oliveira Antonio CP verfasserin aut Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia 2012 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p< microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins Neurology. Diseases of the nervous system Candelario-Jalil Eduardo verfasserin aut Langbein Julia verfasserin aut Wendeburg Lena verfasserin aut Bhatia Harsharan S verfasserin aut Schlachetzki Johannes CM verfasserin aut Biber Knut verfasserin aut Fiebich Bernd L verfasserin aut In Journal of Neuroinflammation BMC, 2004 9(2012), 1, p 2 (DE-627)391784781 (DE-600)2156455-3 17422094 nnns volume:9 year:2012 number:1, p 2 https://doi.org/10.1186/1742-2094-9-2 kostenfrei https://doaj.org/article/b6c84376d15441689031a6dac0e491e0 kostenfrei http://www.jneuroinflammation.com/content/9/1/2 kostenfrei https://doaj.org/toc/1742-2094 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 9 2012 1, p 2
language	English
source	In Journal of Neuroinflammation 9(2012), 1, p 2 volume:9 year:2012 number:1, p 2
sourceStr	In Journal of Neuroinflammation 9(2012), 1, p 2 volume:9 year:2012 number:1, p 2
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins Neurology. Diseases of the nervous system
isfreeaccess_bool	true
container_title	Journal of Neuroinflammation
authorswithroles_txt_mv	de Oliveira Antonio CP @@aut@@ Candelario-Jalil Eduardo @@aut@@ Langbein Julia @@aut@@ Wendeburg Lena @@aut@@ Bhatia Harsharan S @@aut@@ Schlachetzki Johannes CM @@aut@@ Biber Knut @@aut@@ Fiebich Bernd L @@aut@@
publishDateDaySort_date	2012-01-01T00:00:00Z
hierarchy_top_id	391784781
id	DOAJ032769865
language_de	englisch
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Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. 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callnumber-first	R - Medicine
author	de Oliveira Antonio CP
spellingShingle	de Oliveira Antonio CP misc RC346-429 misc microglia misc phosphatidylinositol 3-kinase misc mammalian target of rapamycin misc glycogen synthase kinase-3 misc Akt misc prostaglandins misc Neurology. Diseases of the nervous system Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia
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topic_title	RC346-429 Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia microglia phosphatidylinositol 3-kinase mammalian target of rapamycin glycogen synthase kinase-3 Akt prostaglandins
topic	misc RC346-429 misc microglia misc phosphatidylinositol 3-kinase misc mammalian target of rapamycin misc glycogen synthase kinase-3 misc Akt misc prostaglandins misc Neurology. Diseases of the nervous system
topic_unstemmed	misc RC346-429 misc microglia misc phosphatidylinositol 3-kinase misc mammalian target of rapamycin misc glycogen synthase kinase-3 misc Akt misc prostaglandins misc Neurology. Diseases of the nervous system
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title	Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia
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title_full	Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia
author_sort	de Oliveira Antonio CP
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author_browse	de Oliveira Antonio CP Candelario-Jalil Eduardo Langbein Julia Wendeburg Lena Bhatia Harsharan S Schlachetzki Johannes CM Biber Knut Fiebich Bernd L
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title_sort	pharmacological inhibition of akt and downstream pathways modulates the expression of cox-2 and mpges-1 in activated microglia
callnumber	RC346-429
title_auth	Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia
abstract	<p<Abstract</p< <p<Background</p< <p<Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p<
abstractGer	<p<Abstract</p< <p<Background</p< <p<Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p<
abstract_unstemmed	<p<Abstract</p< <p<Background</p< <p<Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E<sub<2 </sub<and PGD<sub<2</sub<.</p< <p<Findings</p< <p<We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE<sub<2 </sub<and PGD<sub<2 </sub<without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE<sub<2 </sub<and PGD<sub<2</sub<. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE<sub<2 </sub<and PGD<sub<2 </sub<levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE<sub<2 </sub<in non-stimulated microglia.</p< <p<Conclusion</p< <p<Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p<
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Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia

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