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当帕金森患者出现临床症状时,其黑质致密部的绝大部分多巴胺神经元已发生退行性改变。这提示可能存在某些代偿机制,延缓了临床症状的出现。本研究制作6-羟多巴胺诱导的偏侧帕金森大鼠模型,观察位于黑质下网状部和苍白球的激活的小胶质细胞在代偿机制中的作用。研究发现,在偏侧帕金森大鼠中,黑质下网状部聚集的激活的小胶质细胞远多于苍白球中。激活的小胶质细胞胞体增大并表达吞噬物标志物CD68和NG2蛋白多糖。激活的小胶质细胞聚集在黑质下网状部的特定部位,该部位的突触蛋白I和突触后密集蛋白95的表达降低。活化的小胶质细胞吞噬突触前、后膜上的各种蛋白,包括NMDA受体。将红色荧光标记物Di I作为顺行示踪剂注入丘脑底核,可见黑质下网状部和苍白球内的细胞吞噬了Di I。在谷氨酸刺激下,原代培养的小胶质细胞吞噬活动增强,编码吞噬相关因子的m RNA转录水平也增加。人工合成的糖皮质激素地塞米松可以减弱这种改变。给PD大鼠皮下注射地塞米松,可以抑制黑质下网状部小胶质细胞的活化,运动功能障碍进一步加重,谷氨酸能突触转录m RNA增加,GABA能突触转录m RNA水平未增加。这些发现提示,当谷氨酸能神经元活动增强时,黑质下网状部和苍白球的小胶质细胞活化,选择性吞噬丘脑底核的谷氨酸能突触。因此,在基底核区可能存在一个负反馈环路,间接地代偿了由于多巴胺能神经元丢失而导致的功能障碍。小胶质细胞在这个负反馈环路中扮演了重要的角色。
When Parkinson’s patients have clinical symptoms, most of dopamine neurons in the substantia nigra pars compacta have been degeneratively altered. This suggests that there may be some compensatory mechanism, delayed the emergence of clinical symptoms. In this study, 6-hydroxydopamine-induced rat model of unilateral Parkinson’s disease was made to observe the role of activated microglial cells located in the substantia nigra pars reticulum and globus pallidus in compensatory mechanism. The study found that in the parkinsonian rats, the substantia nigra reticular part of the accumulation of activated microglia much more than in the globus pallidus. Activated microglial cell bodies enlarge and express phagocytic markers CD68 and NG2 proteoglycans. Activated microglia accumulate at a specific site of the substantia nigra mesh, and the expression of synapsin I and postsynaptic dense protein 95 at this site is reduced. Activated microglia phagocytose various proteins on the pre and post synapses, including NMDA receptors. The red fluorescent label Di I was injected into the subthalamic nucleus as an antecedent tracer, showing that Di I was phagocytosed by cells in the substantia nigra and the globus pallidus. Under the stimulation of glutamate, the primary cultured microglia phagocytosis activity increased, phagocytosis-related factors m RNA transcription level also increased. Synthetic glucocorticoids dexamethasone attenuated this change. Subcutaneous injection of dexamethasone to PD rats can inhibit the activation of microglia in the substantia nigra at the reticular microglia, further aggravating motor dysfunction, increase of glutamate synaptic transcriptional m RNA, increase of GABAergic synaptic transcriptional m RNA levels Not added. These findings suggest that when glutamatergic neurons are activated, the microglial cells in the substantia nigra and the globus pallidus activate and glutamate synapses selectively engulf the subthalamic nucleus. Thus, there may be a negative feedback loop in the basal ganglia that indirectly compensates for dysfunction due to the loss of dopaminergic neurons. Microglia play an important role in this negative feedback loop.