Suk Kyoungho, Lee Heasuk, Kang Sang Soo, Cho Gyeong Jae, Choi Wan Sung
Department of Anatomy and Neurobiology, College of Medicine, Gyeongsang National University, 92 Chilam-dong, Jinju, Kyungnam 660-751, Korea.
J Pharmacol Exp Ther. 2003 May;305(2):638-45. doi: 10.1124/jpet.102.047373. Epub 2003 Jan 21.
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.
黄芩素（5,6,7-三羟基黄酮）是一种源自中药黄芩根部的黄酮类化合物，已被证明具有抗炎和抗氧化作用，并且是一种著名的12-脂氧合酶抑制剂。我们之前曾报道，神经胶质细胞在炎症激活后会经历一氧化氮（NO）依赖性和非NO依赖性凋亡。在当前的研究中，我们探究了具有抗炎作用的黄芩素如何影响活化小胶质细胞的自调节凋亡及其NO生成。黄芩素可减轻脂多糖（LPS）激活而非干扰素-γ激活的BV-2小鼠小胶质细胞以及大鼠原代小胶质细胞培养物中的NO生成和凋亡。黄芩素对NO生成的抑制作用是由于诱导型NO合酶诱导的抑制。此外，黄芩素抑制BV-2细胞中LPS诱导的核因子-κB（NF-κB）活性，而不影响半胱天冬酶-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-κB的p65亚基转染BV-2细胞消除了黄芩素的凋亡减轻作用，表明抑制NF-κB是主要作用机制。然而，黄芩素对NO供体介导的细胞毒性没有显著影响，并且黄芩素的凋亡减轻作用与12-脂氧合酶抑制无关。基于我们之前的发现，即小胶质细胞的激活诱导细胞死亡（AICD）通过两条独立途径（NO依赖性途径和半胱天冬酶-11依赖性途径）发生，我们目前的结果表明，黄芩素通过抑制细胞毒性NO生成选择性抑制活化小胶质细胞的NO依赖性凋亡途径。此外，黄芩素的AICD抑制作用对激活小胶质细胞的炎症刺激具有特异性。
