Liu B, Du L, Kong L Y, Hudson P M, Wilson B C, Chang R C, Abel H H, Hong J S
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, NC 27709, Research Triangle Park, USA.
Neuroscience. 2000;97(4):749-56. doi: 10.1016/s0306-4522(00)00057-9.
An inflammatory response in the CNS mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. Using mouse cortical mixed glia cultures, we have previously demonstrated that the bacterial endotoxin lipopolysaccharide induces the activation of microglia and the production of proinflammatory factors. Naloxone, an opioid receptor antagonist, inhibits the lipopolysaccharide-induced activation of microglia and the production of proinflammatory factors. Using neuron-glia co-cultures, we extended our study to determine if naloxone has a neuroprotective effect against lipopolysaccharide-induced neuronal damage and analysed the underlying mechanism of action for its potential neuroprotective effect. Pretreatment of cultures with naloxone (1 microM) followed by treatment with lipopolysaccharide significantly inhibited the lipopolysaccharide-induced production of nitric oxide and the release of tumor necrosis factor-alpha, and significantly reduced the lipopolysaccharide-induced damage to neurons. More importantly, both naloxone and its opioid-receptor ineffective enantiomer (+)-naloxone were equally effective in inhibiting the lipopolysaccharide-induced generation of proinflammatory factors and the activation of microglia, as well as in the protection of neurons. These results indicate that the neuroprotective effect of naloxone is mediated by its inhibition of microglial activity and may be unrelated to its binding to the classical opioid receptors.
由小胶质细胞激活介导的中枢神经系统炎症反应是神经退行性疾病发展早期的关键事件。利用小鼠皮质混合胶质细胞培养物，我们先前已证明细菌内毒素脂多糖可诱导小胶质细胞激活并产生促炎因子。阿片受体拮抗剂纳洛酮可抑制脂多糖诱导的小胶质细胞激活和促炎因子产生。利用神经元-胶质细胞共培养物，我们扩展研究以确定纳洛酮是否对脂多糖诱导的神经元损伤具有神经保护作用，并分析其潜在神经保护作用的潜在作用机制。用纳洛酮（1微摩尔）预处理培养物，随后用脂多糖处理，可显著抑制脂多糖诱导的一氧化氮产生和肿瘤坏死因子-α释放，并显著减少脂多糖诱导的神经元损伤。更重要的是，纳洛酮及其阿片受体无效对映体（+）-纳洛酮在抑制脂多糖诱导的促炎因子生成和小胶质细胞激活以及保护神经元方面同样有效。这些结果表明，纳洛酮的神经保护作用是通过其对小胶质细胞活性的抑制介导的，可能与其与经典阿片受体的结合无关。
