Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia.
BACKGROUND
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) E2 and PGD2.


RESULTS
We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE2 and PGD2 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 PGE2 and PGD2. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE2 and PGD2 levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE2 in non-stimulated microglia.


CONCLUSIONS
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.
Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstr, 5, D-79104 Freiburg, Germany.
Antonio C P
AC
de Oliveira
Eduardo
E
Candelario-Jalil
Julia
J
Langbein
Lena
L
Wendeburg
Harsharan S
HS
Bhatia
Johannes C M
JC
Schlachetzki
Knut
K
Biber
Bernd L
BL
Fiebich
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011134:Polysaccharides / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D011134:Polysaccharides; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases