Department of Anatomy and Developmental Biology, Medical Faculty Mannheim of Heidelberg University, Ludolf-Krehl-Str. 7-11, 68167 Mannheim, Germany; Department of Anatomy, Faculty of Medicine, Trakia University, Armeyska 11, 6000 Stara Zagora, Bulgaria.
Department of Anatomy, Faculty of Medicine, Trakia University, Armeyska 11, 6000 Stara Zagora, Bulgaria; Institute of Anatomy and Embryology, University Medical Center Göttingen, Kreuzbergring 36, 37075 Göttingen, Germany.
Exp Neurol. 2019 Aug;318:135-144. doi: 10.1016/j.expneurol.2019.04.013. Epub 2019 Apr 25.
Inhibitors of cell cycle proteins are known to reduce glial activation and to be neuroprotective in a number of settings. In the context of intracerebral grafting, glial activation is documented to correlate with graft rejection. However, the effects of modification of glial reactivity following grafting in the CNS are poorly understood. Moreover, it is not completely clear if the glial cells themselves trigger the rejection process, or are they secondarily activated. The present study investigated the effect of microglial inhibition by the cyclin-dependant kinase 5 (CDK5) inhibitor roscovitine following intracerebral transplantation in the rodent model of Parkinson's disease. Single cell suspension of rat E14 ventral mesencephalic tissue was transplanted to the dopamine-depleted striatum of unilaterally 6-hydroxydopamine (6-OHDA) lesioned male Sprague-Dawley rats. Experimental animals received injections of roscovitine (20 mg/kg) or a vehicle solution three times following the procedure. Immunohistochemistry was carried out on Day 7 and Day 28 to quantitatively describe the glial reaction adjacent to grafts. The data confirm that systemic roscovitine treatment significantly reduced microglial recruitment adjacent to the grafts on Day 28, without exhibiting significant effects on astroglia. However, this was not found to correlate with elevated numbers of neurons in the grafts. Moreover, microglial reaction surrounding grafts was less pronounced compared to control animals, subjected to the mechanical influence only, even without roscovitine treatment. Our results are the first to show the effect of cell cycle inhibition in the context of neuronal transplantation. The findings suggest that microglial activation around intracerebral grafts can be modified pharmacologically. However, the results do not confirm direct neuroprotective effects of cell cycle inhibition after intracerebral transplantation. Reducing microglial recruitment around grafts could be beneficial by reducing inflammation-related degenerative processes. Sparing astrocytes in the same time provides transplanted cells with essential trophics and support. We consider microglial inhibition to be a possible approach for reducing later graft-related complications.
细胞周期蛋白抑制剂已被证实可减少多种情况下的神经胶质细胞激活并具有神经保护作用。在脑内移植的背景下，神经胶质细胞激活与移植物排斥相关。然而，在中枢神经系统中移植后神经胶质反应的改变的影响尚未被充分理解。此外，尚不完全清楚是神经胶质细胞本身触发了排斥过程，还是它们被继发激活。本研究调查了细胞周期依赖性激酶 5（CDK5）抑制剂罗克洛维汀（roscovitine）抑制小胶质细胞后对啮齿动物帕金森病模型脑内移植的影响。将大鼠 E14 腹侧中脑组织的单细胞悬液移植到单侧 6-羟多巴胺（6-OHDA）损伤的雄性 Sprague-Dawley 大鼠的多巴胺耗竭纹状体中。实验动物在手术后三次接受罗克洛维汀（20mg/kg）或载体溶液的注射。在第 7 天和第 28 天进行免疫组织化学染色，以定量描述移植物附近的神经胶质反应。数据证实，全身性罗克洛维汀处理可显著减少第 28 天移植物附近的小胶质细胞募集，但对星形胶质细胞无明显影响。然而，这与移植物中神经元数量的增加无关。此外，与仅接受机械影响的对照动物相比，即使没有罗克洛维汀治疗，移植物周围的小胶质细胞反应也不那么明显。我们的结果首次显示了细胞周期抑制在神经元移植中的作用。研究结果表明，可以通过药理学方法改变脑内移植物周围的小胶质细胞激活。然而，结果并未证实脑内移植后细胞周期抑制的直接神经保护作用。减少移植物周围小胶质细胞的募集可以通过减少与炎症相关的退行性过程而获益。同时保留星形胶质细胞可为移植细胞提供必要的营养和支持。我们认为小胶质细胞抑制可能是减少后期移植物相关并发症的一种方法。
