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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.
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Authors | Eri Kawashita, Daisuke Tsuji, Masahiro Toyoshima, Yosuke Kanno, Hiroyuki Matsuno, Kohji Itoh |
Journal | PloS one
(PLoS One)
Vol. 6
Issue 1
Pg. e16269
(Jan 27 2011)
ISSN: 1932-6203 [Electronic] United States |
PMID | 21298000
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Chemokine CCL3
- Chemokines
- Cyclic AMP-Dependent Protein Kinases
- Dinoprostone
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Topics |
- Animals
- Chemokine CCL3
(biosynthesis)
- Chemokines
(biosynthesis)
- Cyclic AMP-Dependent Protein Kinases
(metabolism)
- Dinoprostone
(pharmacology)
- Disease Models, Animal
- Inflammation
(etiology)
- Mice
- Microglia
(metabolism)
- Sandhoff Disease
(metabolism)
- Signal Transduction
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