1 Shefa Neuroscience Research Center, Khatam-Alanbia Hospital, Tehran, Iran.
2 Department of Virology, Golestan University of Medical Sciences, Gorgan, Iran.
Cephalalgia. 2018 Apr;38(4):626-638. doi: 10.1177/0333102417702132. Epub 2017 Apr 3.
Background Cortical spreading depression (CSD) related diseases such as migraine, cerebrovascular diseases, and epilepsy have been associated with reactive astrocytosis, yet the mechanisms of these tissue changes remain unclear. CSD-induced inflammatory response has been proposed to play a role in some neurological disorders and thus may also contribute to reactive astrocytosis. Methods Using ex vivo brain slices and in vitro astrocytic cultures, we aimed to characterize CSD related changes in astrocytes and markers of inflammation by immunocyto- and immunohistochemistry. CSD was induced by application of KCl (3 mol/l) on neocortical tissues. The application of KCl was repeated weekly over the course of four weeks. Results CSD induced an increase in the mean number and volume of astrocytes in rat brain tissue when compared to controls, whereas no changes in neuronal numbers and volumes were seen. These cell-type specific changes, suggestive of reactive astrocytosis, were paralleled by an increased expression of protein markers indicative of astrocytes and neuroinflammation in ex vivo brain slices of animals undergoing CSD when compared to sham-treated controls. Cultured astrocytes showed an increased expression of the immune modulatory enzyme indoleamine 2,3-dioxygenase and an elevated expression of the pro-inflammatory markers, IL-6, IL-1β, and TNFα in addition to increased levels of toll like receptors (TLR3 and TLR4) and astrocytic markers after induction of CSD. Conclusion These findings indicate that CSD related reactive astrocytosis is linked to an upregulation of inflammatory markers. Targeting inflammation with already approved and available immunomodulatory treatments may thus represent a strategy to combat or ameliorate CSD-related disease.
皮质扩散性抑制（CSD）相关疾病，如偏头痛、脑血管疾病和癫痫，与反应性星形胶质细胞有关，但这些组织变化的机制尚不清楚。CSD 诱导的炎症反应被认为在一些神经疾病中起作用，因此也可能导致反应性星形胶质细胞。方法：我们使用离体脑片和体外星形胶质细胞培养物，通过免疫细胞化学和免疫组织化学来描述 CSD 相关的星形胶质细胞和炎症标志物的变化。CSD 通过在新皮质组织上施加 KCl（3mol/L）来诱导。KCl 的施加每周重复一次，共进行四周。结果：与对照组相比，CSD 诱导大鼠脑组织中星形胶质细胞的平均数量和体积增加，而神经元数量和体积没有变化。这些细胞类型特异性的变化，提示反应性星形胶质细胞，与在接受 CSD 的动物的离体脑片中，与假手术对照组相比，指示星形胶质细胞和神经炎症的蛋白质标志物的表达增加相平行。培养的星形胶质细胞在诱导 CSD 后表现出免疫调节酶吲哚胺 2,3-双加氧酶的表达增加，以及促炎标志物 IL-6、IL-1β 和 TNFα 的表达增加，此外，还增加了 Toll 样受体（TLR3 和 TLR4）和星形胶质细胞标志物的表达。结论：这些发现表明，CSD 相关的反应性星形胶质细胞与炎症标志物的上调有关。用已经批准和可用的免疫调节治疗来靶向炎症，可能代表了一种对抗或改善 CSD 相关疾病的策略。
