Arai Kunizo, Wood John P M, Osborne Neville N
Nuffield Laboratory of Ophthalmology, University of Oxford, Walton Street, Oxford OX2 6AW, UK.
Brain Res. 2003 Sep 26;985(2):176-86. doi: 10.1016/s0006-8993(03)03156-1.
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 gamma-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 beta(2)- (ICI-18551), beta(1)- (betaxolol) and mixed beta(1)/beta(2)- (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 beta-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. beta-adrenergic receptor agonists prevent the effects of LPS by inhibiting the stimulation of nitric oxide production. The data also suggest that beta-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.
研究表明，用脂多糖（LPS）处理6日龄视网膜培养物72小时，可使一氧化氮生成呈剂量依赖性增加。同时，通过乳酸脱氢酶（LDH）释放及TUNEL法检测神经元标记物增加所确定的细胞死亡也升高。处理期间，胶质细胞中诱导型一氧化氮合酶和胶质纤维酸性蛋白标记物均增加，γ-氨基丁酸阳性神经元数量减少。一氧化氮合酶抑制剂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及细胞死亡。在本研究中，β₂-（ICI-18551）、β₁-（倍他洛尔）及β₁/β₂-混合型（噻吗洛尔、美替洛尔）肾上腺素能受体拮抗剂均显示可减弱LPS诱导的这些培养物中LDH的释放，但对LPS刺激的一氧化氮生成无影响。钙通道阻滞剂硝苯地平可模拟此效应。有趣的是，β-肾上腺素能受体激动剂沙丁胺醇、去甲肾上腺素和异丙肾上腺素也能够减弱LPS引起的细胞死亡。此外，这些化合物还抑制LPS刺激的一氧化氮释放。这些研究提示，LPS刺激培养的视网膜胶质细胞释放一氧化氮，此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生成的刺激来预防LPS的作用。数据还提示，β-肾上腺素能受体拮抗剂可减弱LPS诱导的神经元死亡，但这些化合物的作用方式依赖于神经元，可被钙通道阻断所模拟，且与一氧化氮释放的刺激无关。
