Liu B, Du L, Hong J S
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
J Pharmacol Exp Ther. 2000 May;293(2):607-17.
Degeneration of dopaminergicrgic neurons in the substantia nigra of the brain is a hallmark of Parkinson's disease and inflammation and oxidative stress are closely associated with the pathogenesis of degenerative neurological disorders. Treatment of rat mesencephalic mixed neuron-glia cultures with lipopolysaccharide (LPS)-activated microglia, resident immune cells of the brain, to release proinflammatory and neurotoxic factors tumor necrosis factor-alpha, interleukin-1beta, nitric oxide, and superoxide and subsequently caused damage to midbrain neurons, including dopaminergic neurons. The LPS-induced degeneration of the midbrain neurons was significantly reduced by cotreatment with naloxone, an opioid receptor antagonist. This study focused on understanding the mechanism of action for the protective effect of naloxone on dopaminergic neurons because of relevance to Parkinson's disease. Both naloxone and its opioid receptor inactive stereoisomer (+)-naloxone protected the dopaminergic neurons with equal potency. Naloxone inhibited LPS-induced activation of microglia and release of proinflammatory factors, and inhibition of microglia generation of superoxide free radical best correlated with the neuroprotective effect of naloxone isomers. To further delineate the site of action, naloxone was found to partially inhibit the binding of [(3)H]LPS to cell membranes, whereas it failed to prevent damage to dopaminergic neurons by peroxynitrite, a product of nitric oxide and superoxide. These results suggest that naloxone at least in part interferes with the binding of LPS to cell membranes to inhibit microglia activation and protect dopaminergic neurons as well as other neurons in the midbrain cultures from inflammatory damage.
大脑黑质中多巴胺能神经元的退化是帕金森病的一个标志，炎症和氧化应激与退行性神经疾病的发病机制密切相关。用脂多糖（LPS）激活的小胶质细胞（大脑中的常驻免疫细胞）处理大鼠中脑混合神经元-胶质细胞培养物，会释放促炎和神经毒性因子肿瘤坏死因子-α、白细胞介素-1β、一氧化氮和超氧化物，随后对中脑神经元造成损伤，包括多巴胺能神经元。用阿片受体拮抗剂纳洛酮联合处理可显著减少LPS诱导的中脑神经元退化。由于与帕金森病相关，本研究着重于了解纳洛酮对多巴胺能神经元保护作用的作用机制。纳洛酮及其阿片受体无活性的立体异构体（+）-纳洛酮以同等效力保护多巴胺能神经元。纳洛酮抑制LPS诱导的小胶质细胞激活和促炎因子释放，而抑制小胶质细胞产生超氧自由基与纳洛酮异构体的神经保护作用最相关。为了进一步确定作用位点，发现纳洛酮可部分抑制[（3）H]LPS与细胞膜的结合，而它不能防止一氧化氮和超氧化物的产物过氧亚硝酸盐对多巴胺能神经元的损伤。这些结果表明，纳洛酮至少部分地干扰LPS与细胞膜的结合，以抑制小胶质细胞激活，并保护中脑培养物中的多巴胺能神经元以及其他神经元免受炎症损伤。
