Suppression of lipopolysaccharide-induced microglial activation by a benzothiazole derivative.
We previously reported that KHG21834, a benzothiazole derivative, attenuates the beta-amyloid (Abeta)-induced degeneration of both cortical and mesencephalic neurons in vitro. Central nervous system inflammation mediated by activated microglia is a key event in the development of neurodegenerative disease. In this study, we show that KHG21834 suppresses inflammation-mediated cytokine upregulation. Specifically, KHG21834 induces significant reductions in the lipopolysaccharide-induced activation of microglia and production of proinflammatory mediators such as tumor necrosis factor-alpha, interlukin-1beta, nitric oxide, and inducible nitric oxide synthase. In addition, KHG21834 blocks the expression of mitogen-activated protein kinases, including ERK, p38 MAPK, JNK, and Akt. In vivo intracerebroventricular infusion of KHG21834 also leads to decreases the level of interleukin-1beta and tumor necrosis factor-alpha in brain. These results, in combination with our previous findings on Abeta-induced degeneration, support the potential therapeutic efficacy of KHG21834 for the treatment of neurodegenerative disorders via the targeting of key glial activation pathways.
Kim
Eun-A
EA
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
Kim
Hanwook
H
Ahn
Jee-Yin
JY
Hahn
Hoh-Gyu
HG
Kim
Key-Sun
KS
Kim
Tae Ue
TU
Cho
Sung-Woo
SW
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
D052160:Benzothiazoles; D016207:Cytokines; C524157:KHG21834; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D051058:Oncogene Protein v-akt; D020928:Mitogen-Activated Protein Kinases