Flavonoid baicalein attenuates activation-induced cell death of brain microglia
Flavonoid baicalein attenuates activation-induced cell death of brain microglia
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DOI：
10.1124/jpet.102.047373
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发表时间：
2003-05-01
影响因子：
3.5
通讯作者：
Choi, WS
中科院分区：
文献类型：
--
作者：
Suk, K;Lee, H;Choi, WS
黄芩素（5，6，7-三羟基黄酮）是一种来源于中草药黄芩的黄酮类化合物，具有抗炎和抗氧化作用，是一种众所周知的12-脂氧合酶抑制剂。我们以前曾报道，神经胶质细胞发生一氧化氮（NO）依赖性和NO非依赖性细胞凋亡炎症激活。在目前的工作中，我们问抗炎黄芩素如何影响激活的小胶质细胞的自动调节凋亡及其NO的产生。黄芩素减弱了脂多糖（LPS）激活的BV-2小鼠小胶质细胞和大鼠原代小胶质细胞培养物的NO产生和凋亡，但没有干扰素-γ激活。黄芩素抑制NO生成是由于抑制诱导型NO合成酶的诱导。此外，黄芩素抑制LPS诱导的BV-2细胞核因子-κ B（NF-κ B）活性，而不影响caspase-11激活，干扰素调节因子-1诱导，或信号转导和转录激活因子-1磷酸化。用NF-κ B的p65亚基转染BV-2细胞可消除黄芩素的抗凋亡作用，表明NF-κ B的抑制是主要的作用机制。然而，黄芩素并没有显着影响NO供体介导的细胞毒性，黄芩素的细胞毒性衰减作用是独立的12-脂氧合酶抑制。基于我们以前的研究结果，激活诱导的细胞死亡（AICD）的小胶质细胞发生通过两个独立的途径（NO依赖的途径和caspase-11依赖的途径），我们目前的研究结果表明，黄芩素选择性抑制NO依赖的活化小胶质细胞的细胞凋亡途径，通过抑制细胞毒性NO的产生。此外，黄芩素的AICD抑制作用是特异性的炎症刺激，激活小胶质细胞。
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.