Transsynaptic anterograde and retrograde degeneration of neurons and neural fibers are assumed to trigger local excitotoxicity and inflammatory processes. These processes in turn are thought to drive exo-focal neurodegeneration in remote areas connected to the infarcted tissue after ischemic stroke. In the case of middle cerebral artery occlusion (MCAO), in which striato-nigral connections are affected, the hypothesis of inflammation-induced remote neurodegeneration is based on the temporal dynamics of an early appearance of inflammatory markers in midbrain followed by dopaminergic neuronal loss. To test the hypothesis of a direct transsynaptic mediation of secondary exo-focal post-ischemic neurodegeneration, we used a photochemical induction of a stroke (PTS) in Sprague-Dawley rats restricted to motor cortex (MC), thereby sparing the striatal connections to dopaminergic midbrain nuclei. To dissect the temporal dynamics of post-ischemic neurodegeneration, we analyzed brain sections harvested at day 7 and 14 post stroke. Here, an unexpectedly pronounced and widespread loss of dopaminergic neurons occurred 14 days after stroke also affecting dopaminergic nuclei that are not directly coupled to MC. Since the pattern of neurodegeneration in case of a pure motor stroke is similar to a major stroke including the striatum, it is unlikely that direct synaptic coupling is a prerequisite for delayed secondary exo-focal post ischemic neurodegeneration. Furthermore, dopaminergic neurodegeneration was already detected by Fluoro-Jade C staining at day 7, coinciding with a solely slight inflammatory response. Thus, inflammation cannot be assumed to be the primary driver of exo-focal post-ischemic cell death. Moreover, nigral substance P (SP) expression indicated intact striato-nigral innervation after PTS, whereas opposing effects on SP expression after striatal infarcts argue against a critical role of SP in neurodegenerative or inflammatory processes during exo-focal neurodegeneration.

中文翻译：

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单纯运动性皮层卒中后，继发性继发性局灶性多巴胺能神经变性发生在未直接连接的中脑核中。

假定神经元和神经纤维的突触顺行和逆行变性触发局部兴奋性毒性和炎症过程。继而认为这些过程可在缺血性中风后驱动与梗塞组织相连的偏远地区的局灶性神经变性。在纹状体-黑色连接受到影响的大脑中动脉闭塞（MCAO）的情况下，炎症诱导的远端神经变性的假说是基于中脑中炎症标志物早期出现，随后多巴胺能神经元丧失的时间动态。为了测试继发性局灶性局部缺血后神经变性直接经突触介导的假说，我们在受运动皮层（MC）限制的Sprague-Dawley大鼠中使用了光化学诱导的中风（PTS），从而减少纹状体与多巴胺能中脑核的连接。为了剖析缺血性神经变性后的时间动态，我们分析了中风后第7天和第14天收获的大脑切片。在此，中风后14天发生了多巴胺能神经元的意外明显和广泛丧失，这也影响了未直接与MC偶联的多巴胺能核。由于纯运动性卒中时神经退行性变的模式与包括纹状体在内的主要中风相似，因此直接突触耦合不可能成为继发性局灶性局部缺血后继发性神经退行性变的先决条件。此外，在第7天已经通过Fluoro-Jade C染色检测到了多巴胺能神经变性，这与轻微的炎症反应相吻合。从而，不能认为炎症是局灶性缺血后细胞死亡的主要驱动力。此外，黑质物质P（SP）的表达表明PTS后完整的纹状体-黑色神经支配，而纹状体梗死后对SP表达的相反作用则反对SP在局灶性神经变性期间在神经变性或炎症过程中的关键作用。