β-Adrenergic receptor agonists and antagonists counteract LPS-induced neuronal death in retinal cultures by different mechanisms
β-Adrenergic receptor agonists and antagonists counteract LPS-induced neuronal death in retinal cultures by different mechanisms
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DOI：
10.1016/s0006-8993(03)03156-1
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发表时间：
2003-09
期刊：
影响因子：
2.9
通讯作者：
K. Arai;J. Wood;N. Osborne
中科院分区：
文献类型：
--
作者：
K. Arai;J. Wood;N. Osborne
脂多糖 (LPS) 处理 72 小时显示出剂量依赖性地增加 6 天视网膜培养物中一氧化氮的产生。通过乳酸脱氢酶 (LDH) 释放和 TUNEL 神经元标记增加确定的细胞死亡同时增加。治疗期间，神经胶质细胞中诱导型一氧化氮合酶和神经胶质原纤维酸性蛋白标记均增加，γ-氨基丁酸阳性神经元数量减少。 NOS 抑制剂、N-硝基-L-精氨酸甲酯、地塞米松和吲哚美辛可有效抑制 LPS 引起的一氧化氮刺激和细胞死亡。在这项研究中，β2- (ICI-18551)、β1-（倍他洛尔）和混合 β1/β2-（噻吗洛尔、美替洛尔）肾上腺素能受体拮抗剂均能减弱 LPS 诱导的 LDH 从这些培养物中的释放，但对 LPS 刺激的一氧化氮产生没有影响。钙通道阻滞剂硝苯地平模仿了这种效应。有趣的是，β-肾上腺素能受体激动剂沙丁胺醇、动脉肾上腺和异丙肾上腺素也能够减轻脂多糖引起的细胞死亡。此外，这些化合物还抑制脂多糖刺激的一氧化氮释放。这些研究表明，LPS 刺激培养的视网膜神经胶质细胞释放一氧化氮，并且该过程导致神经元死亡。 β-肾上腺素能受体激动剂通过抑制一氧化氮产生的刺激来防止脂多糖的作用。数据还表明，β-肾上腺素能受体拮抗剂可以减轻 LPS 诱导的神经元死亡，但这些化合物的作用方式是神经元依赖性的，通过钙通道的阻断来模拟，并且不依赖于一氧化氮释放的刺激。
Treatment with lipopolysaccharide (LPS) for 72 h was shown to dose-dependently increase nitric oxide production from 6-day-old retinal cultures. Cell death, as determined by lactate dehydrogenase (LDH) release and an increase in neuronal labelling for TUNEL, was elevated concurrently. During treatment there was an increase of both inducible nitric oxide synthase and glial fibrillary acidic protein labelling in glial cells and a reduction in the number of γ-aminobutyric acid-positive neurones. The NOS inhibitors, N-nitro-l-arginine methyl ester, dexamethasone and indomethacin potently inhibited both nitric oxide stimulation and cell death caused by LPS. In this study, the β2- (ICI-18551), β1- (betaxolol) and mixed β1/β2- (timolol, metipranolol) adrenergic receptor antagonists were all shown to attenuate LPS-induced LDH release from these cultures, but to have no effect on LPS-stimulated nitric oxide production. This effect was mimicked by the calcium channel blocker, nifedipine. Interestingly, the β-adrenergic receptor agonists, salbutamol, arterenol and isoproterenol were also able to attenuate cell death caused by LPS. Moreover, these compounds also inhibited LPS-stimulated nitric oxide release. These studies suggest that LPS stimulates nitric oxide release from cultured retinal glial cells and that this process leads to neurone death. β-adrenergic receptor agonists prevent the effects of LPS by inhibiting the stimulation of nitric oxide production. The data also suggest that β-adrenergic receptor antagonists can attenuate LPS-induced death of neurones, but that these compounds act in a manner that is neurone-dependent, is mimicked by blockade of calcium channels and is independent of the stimulation of nitric oxide release.