Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats
Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats
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DOI：
10.1016/s0306-4522(00)00033-6
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发表时间：
2000-01-01
期刊：
影响因子：
3.3
通讯作者：
Hagg, T
中科院分区：
文献类型：
--
作者：
Lu, X;Bing, G;Hagg, T
常驻小胶质细胞参与中枢神经系统的免疫反应，并可能导致神经元变性和死亡。在这里，我们测试了在成年大鼠黑质上方注射细菌脂多糖（引起炎症和小胶质细胞激活）是否会导致多巴胺能黑质致密部神经元死亡。注射脂多糖两周后，整个黑质小胶质细胞明显激活，黑质逆行标记神经元的数量减少到正常的66%。这表明炎症和/或小胶质细胞激活可导致成熟动物模型中的神经元细胞死亡。据报道，阿片受体拮抗剂纳洛酮减少小胶质细胞释放细胞毒性物质，并在体外保护皮质神经元。在这里，连续两周在黑质附近以微摩尔浓度输注纳洛酮，阻止了大部分由脂多糖引起的神经元死亡，即85%的神经元存活。此外，全身（皮下）输注0.1 mg/d纳洛酮，94%的神经元存活。纳洛酮对小胶质细胞活化的形态学影响不明显，提示纳洛酮减少了小胶质细胞源性细胞毒性物质的释放。或者，小胶质细胞可能不会导致神经元丢失，或者纳洛酮可能通过阻断（多巴胺能或gaba能）神经元上的阿片受体起作用。因此，局部炎症诱导和阿片拮抗剂纳洛酮阻止成年大鼠多巴胺能黑质神经元的死亡。这可能与帕金森病的病理和治疗的理解有关，这些神经元退化。(c) 2000 ibro。Elsevier Science Ltd.出版。
Resident microglia are involved in immune responses of the central nervous system and may contribute to neuronal degeneration and death. Here, we tested in adult rats whether injection of bacterial lipopolysaccharide (which causes inflammation and microglial activation) just above the substantia nigra, results in the death of dopaminergic substantia nigra pars compacta neurons. Two weeks after lipopolysaccharide injection, microglial activation was evident throughout the nigra and the number of retrogradely-labeled substantia nigra neurons was reduced to 66% of normal. This suggests that inflammation and/or microglial activation can lead to neuronal cell death in a well-defined adult animal model. The opioid receptor antagonist naloxone reportedly reduces release of cytotoxic substances from microglia and protects cortical neurons in vitro. Here, a continuous two-week infusion of naloxone at a micromolar concentration close to the substantia nigra, prevented most of the neuronal death caused by lipopolysaccharide, i.e. 85% of the neurons survived. In addition, with systemic (subcutaneous) infusion of 0.1 mg/d naloxone, 94% of the neurons survived. Naloxone infusions did not obviously affect the morphological signs of microglial activation, suggesting that naloxone reduces the release of microglial-derived cytotoxic substances. Alternatively, microglia might not cause the neuronal loss, or naloxone might act by blocking opioid receptors on (dopaminergic or GABAergic) neurons.Thus, local inflammation induces and the opioid antagonist naloxone prevents the death of dopaminergic substantia nigra neurons in adult rats. This may be relevant to the understanding of the pathology and treatment of Parkinson's disease, where these neurons degenerate. (C) 2000 IBRO. Published by Elsevier Science Ltd.