Flavonoid baicalein attenuates activation-induced cell death of brain microglia.
Baicalein (5,6,7-trihydroxyflavone), a flavonoid originated from the root of Chinese medicinal herb Scutellaria baicalensis, has been shown to exert anti-inflammatory and antioxidant effects, and it is a well known inhibitor of 12-lipoxygenase. We have previously reported that neuroglia undergo nitric oxide (NO)-dependent and NO-independent apoptosis upon inflammatory activation. In the current work, we asked how anti-inflammatory baicalein influences autoregulatory apoptosis of activated microglia and their NO production. Baicalein attenuated NO production and apoptosis of lipopolysaccharide (LPS)-activated, but not interferon-gamma-activated, BV-2 mouse microglial cells as well as rat primary microglia cultures. The inhibition of NO production by baicalein was due to the suppression of inducible NO synthase induction. Moreover, baicalein inhibited LPS-induced nuclear factor-kappaB (NF-kappaB) activity in BV-2 cells without affecting caspase-11 activation, interferon regulatory factor-1 induction, or signal transducer and activator of transcription-1 phosphorylation. Transfection of BV-2 cells with a p65 subunit of NF-kappaB abolished the apoptosis-attenuating effects of baicalein, indicating that the inhibition of NF-kappaB is a major mechanism of action. Baicalein, however, did not significantly affect NO donor-mediated cytotoxicity, and the apoptosis-attenuating effects of baicalein were independent of 12-lipoxygenase inhibition. Based on our previous findings that activation-induced cell death (AICD) of microglia occurs through two separate pathways (NO-dependent pathway and caspase-11-dependent pathway), our current results suggest that baicalein selectively inhibits the NO-dependent apoptotic pathway of activated microglia by suppressing cytotoxic NO production. Also, the AICD-inhibiting effects of baicalein were specific for the inflammatory stimulus that activated microglia.
Suk
Kyoungho
K
Department of Anatomy and Neurobiology, College of Medicine, Gyeongsang National University, 92 Chilam-dong, Jinju, Kyungnam 660-751, Korea. ksuk@nongae.gsnu.ac.kr
Lee
Heasuk
H
Kang
Sang Soo
SS
Cho
Gyeong Jae
GJ
Choi
Wan Sung
WS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004396:Coloring Agents; D024202:Electrophoretic Mobility Shift Assay; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007202:Indicators and Reagents; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis; D011003:Ploidies; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection; D014343:Trypan Blue
D004396:Coloring Agents; D044950:Flavanones; D005419:Flavonoids; D016166:Free Radical Scavengers; D007202:Indicators and Reagents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013778:Tetrazolium Salts; D013844:Thiazoles; D009569:Nitric Oxide; C006680:baicalein; D007371:Interferon-gamma; D001092:Arachidonate 12-Lipoxygenase; D020169:Caspases; C022616:thiazolyl blue; D014343:Trypan Blue