The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation
The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation
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DOI：
10.1111/j.1460-9568.2005.04220.x
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发表时间：
2005-07-01
影响因子：
3.4
通讯作者：
Jenner, P
中科院分区：
文献类型：
--
作者：
Iravani, MM;Leung, CCM;Jenner, P
持续的反应性小胶质细胞增生可能导致帕金森病 (PD)、暴露于 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 的人和非人灵长类动物中黑质多巴胺能神经元的进行性变性。然而，神经胶质细胞激活和黑质细胞死亡之间的时间关系相对尚未被探索。因此，在大鼠中研究了单侧黑质上脂多糖（LPS）给药诱导的急性（24小时）和慢性（30天）神经胶质细胞活化的影响。 24小时时，LPS给药导致黑质（SN）中酪氨酸羟化酶免疫反应性（TH-ir）神经元数量显着减少，但纹状体TH-ir不受影响。到 30 天时，LPS 处理的黑质中 TH 阳性神经元的损失不大于 24 小时，尽管存在纹状体 TH-ir 的异质损失。黑质纹状体神经元的丧失具有功能意义，因为在 30 天时，LPS 治疗的大鼠表现出响应 (+)-苯丙胺给药而进行的同向转圈。 24小时时，SN中胶质纤维酸性蛋白（GFAP）-ir星形胶质细胞适度增加，但p47phox阳性OX-42-ir小胶质细胞显着升高，并且存在强烈的诱导型一氧化氮合酶（iNOS）-ir和3-硝基酪氨酸（3-NT）-ir。然而，到了30天，OX-42-ir小胶质细胞的形态恢复到静止状态，数量大大减少，并且不存在3-NT-ir。 30天时，GFAP-ir星形胶质细胞数量显着增加，iNOS-ir存在于纤维状星形胶质细胞样细胞中。这项研究表明，导致多巴胺能神经元变性的急性胶质细胞激活是一种急性短暂反应，其本身不会使细胞死亡永久化或导致小胶质细胞激活时间延长。
Sustained reactive microgliosis may contribute to the progressive degeneration of nigral dopaminergic neurons in Parkinson's disease (PD), in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposed human and in non-human primates. However, the temporal relationship between glial cell activation and nigral cell death is relatively unexplored. Consequently, the effects of acute (24 h) and chronic (30 days) glial cell activation induced by unilateral supranigral lipopolysaccharide (LPS) administration were studied in rats. At 24 h, LPS administration caused a marked reduction in the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra (SN) but striatal TH-ir was unaffected. By 30 days, the loss of TH-positive neurons in the LPS-treated nigra was no greater than at 24 h although a heterogeneous loss of striatal TH-ir was present. The loss of nigrostriatal neurons was of functional significance, as at 30 days, LPS-treated rats exhibited ipsiversive circling in response to (+)-amphetamine administration. At 24 h, there was a moderate increase in glial fibrillary acidic protein (GFAP)-ir astrocytes in the SN but a marked elevation of p47phox positive OX-42-ir microglia, and intense inducible nitric oxide synthase (iNOS)-ir and 3-nitrotyrosine (3-NT)-ir was present. However, by 30 days the morphology of OX-42-ir microglia returned to a resting state, the numbers were greatly reduced and no 3-NT-ir was present. At 30 days, GFAP-ir astrocytes were markedly increased in number and iNOS-ir was present in fibrillar astrocyte-like cells. This study shows that acute glial activation leading to dopaminergic neuron degeneration is an acute short-lasting response that does not itself perpetuate cell death or lead to prolonged microglial activation.