College of Medicine and Public Health, Flinders University, GPO Box 2100, Adelaide, SA, 5001, Australia.
Flinders Centre for Epidemiology and Biostatistics, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
J Neuroinflammation. 2021 Jul 31;18(1):168. doi: 10.1186/s12974-021-02208-w.
Following stroke, changes in neuronal connectivity in tissue surrounding the infarct play an important role in both spontaneous recovery of neurological function and in treatment-induced improvements in function. Microglia and astrocytes influence this process through direct interactions with the neurons and as major determinants of the local tissue environment. Subpopulations of peri-infarct glia proliferate early after stroke providing a possible target to modify recovery. Treatment with cell cycle inhibitors can reduce infarct volume and improve functional recovery. However, it is not known whether these inhibitors can influence neurological function or alter the responses of peri-infarct glia without reducing infarction. The present study aimed to address these issues by testing the effects of the cell cycle inhibitor, olomoucine, on recovery and peri-infarct changes following photothrombotic stroke.
Stroke was induced by photothrombosis in the forelimb sensorimotor cortex in Sprague-Dawley rats. Olomoucine was administered at 1 h and 24 h after stroke induction. Forelimb function was monitored up to 29 days. The effects of olomoucine on glial cell responses in peri-infarct tissue were evaluated using immunohistochemistry and Western blotting.
Olomoucine treatment did not significantly affect maximal infarct volume. Recovery of the affected forelimb on a placing test was impaired in olomoucine-treated rats, whereas recovery in a skilled reaching test was substantially improved. Olomoucine treatment produced small changes in aspects of Iba1 immunolabelling and in the number of CD68-positive cells in cerebral cortex but did not selectively modify responses in peri-infarct tissue. The content of the astrocytic protein, vimentin, was reduced by 30% in the region of the lesion in olomoucine-treated rats.
Olomoucine treatment modified functional recovery in the absence of significant changes in infarct volume. The effects on recovery were markedly test dependent, adding to evidence that skilled tasks requiring specific training and general measures of motor function can be differentially modified by some interventions. The altered recovery was not associated with specific changes in key responses of peri-infarct microglia, even though these cells were considered a likely target for early olomoucine treatment. Changes detected in peri-infarct reactive astrogliosis could contribute to the altered patterns of functional recovery.
中风后，梗死周围组织中神经元连接的变化在神经功能的自发恢复和治疗诱导的功能改善中都起着重要作用。小胶质细胞和星形胶质细胞通过与神经元的直接相互作用以及作为局部组织环境的主要决定因素来影响这一过程。梗死周围胶质细胞的亚群在中风后早期增殖，为改变恢复提供了一个可能的靶点。细胞周期抑制剂的治疗可以减少梗死体积并改善功能恢复。然而，尚不清楚这些抑制剂是否可以在不减少梗死的情况下影响神经功能或改变梗死周围胶质细胞的反应。本研究旨在通过测试细胞周期抑制剂olomoucine 对光血栓性中风后恢复和梗死周围变化的影响来解决这些问题。
在 Sprague-Dawley 大鼠的前肢感觉运动皮层通过光血栓形成诱导中风。在中风诱导后 1 小时和 24 小时给予 olomoucine。监测前肢功能至 29 天。使用免疫组织化学和 Western blot 评估 olomoucine 对梗死周围组织中神经胶质细胞反应的影响。
olomoucine 治疗并未显著影响最大梗死体积。在 olomoucine 治疗的大鼠中，受影响的前肢在放置试验中的恢复受到损害，而在熟练的伸展试验中的恢复则大大改善。olomoucine 治疗对 Iba1 免疫标记的某些方面和大脑皮层中 CD68 阳性细胞的数量仅有微小的改变，但并未选择性地改变梗死周围组织的反应。在 olomoucine 治疗的大鼠中，病变区域的星形胶质细胞蛋白 vimentin 的含量减少了 30%。
olomoucine 治疗在不显著改变梗死体积的情况下改变了功能恢复。对恢复的影响明显取决于测试，这进一步证明，熟练的任务需要特定的训练和一般的运动功能测量可以被一些干预措施不同地改变。改变的恢复与梗死周围微胶质细胞的关键反应没有特定的变化相关，尽管这些细胞被认为是早期 olomoucine 治疗的一个可能靶点。在梗死周围反应性星形胶质细胞中检测到的变化可能有助于改变功能恢复的模式。
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