title: Prostaglandin E2 reverses aberrant production of an inflammatory chemokine by microglia from Sandhoff disease model mice through the cAMP-PKA pathway.
abstract: BACKGROUND
  Sandhoff disease (SD) is a neurodegenerative lysosomal β-hexosaminidase (Hex) deficiency involving excessive accumulation of undegraded substrates, including terminal GlcNAc-oligosaccharides and GM2 ganglioside. Microglia-mediated neuroinflammation contributes to the pathogenesis and progression of SD. Our previous study demonstrated that MIP-1α, a putative pathogenic factor for SD, is up-regulated in microglial cells derived from SD model mice (SD-Mg) through activation of Akt and JNK.
  
  
  RESULTS
  In this study, we first demonstrated that prostaglandin E2 (PGE2), which is one of the lipid mediators derived from arachidonic acid and is known to suppress activation of microglia, reduced the aberrant MIP-1α production by SD-Mg to the same level as by WT-Mg. PGE2 also attenuated the activation of Akt and JNK. The inhibition of MIP-1α production and the activation of Akt and JNK occurred through the EP2 and 4/cAMP/PKA signaling pathway in the murine microglia derived from SD model mice.
  
  
  CONCLUSIONS
  We propose that PGE2 plays a role as a negative regulator of MIP-1α production in the pathogenesis of SD, and that PGE2-EP2 and 4/cAMP/PKA signaling could be a target pathway for therapy for SD.
authors.affiliation: Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Kawashita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuji
authors.forename: Masahiro
authors.initials: M
authors.lastname: Toyoshima
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kanno
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsuno
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000818:Animals; D054405:Chemokine CCL3 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000209:etiology*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D012497:Sandhoff Disease / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D054405:Chemokine CCL3; D018925:Chemokines; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone