Department of Neurology, University Hospital Cologne, Kerpener Strasse 62, 50924, Cologne, Germany.
INM-4, Research Centre Juelich, Juelich, Germany.
J Neuroimmune Pharmacol. 2019 Jun;14(2):295-311. doi: 10.1007/s11481-018-9826-1. Epub 2018 Nov 28.
Cortical cerebral ischemia elicits neuroinflammation as well as secondary neuronal degeneration in remote areas. Locally distinct and specific secondary neurodegeneration affecting thalamic nuclei connected to cortical areas highlights such processes. Osteopontin (OPN) is a cytokine-like glycoprotein that is excreted in high amounts after cerebral ischemia and exerts various immunomodulatory functions. We here examined putative protective effects of OPN in secondary thalamic degeneration. We subjected male Wistar rats to photothrombosis and subsequently injected OPN or placebo intracerebroventricularly. Immunohistochemical and fluorescence staining was used to detect the extent of neuronal degeneration and microglia activation. Ex vivo autoradiography with radiotracers available for human in vivo PET studies, i.e., CIS-4-[F]Fluor-D-Proline (D-cis-[F]FPRO), and [6-H]thymidine ([H]thymidine), confirmed degeneration and proliferation, respectively. We found secondary neurodegeneration in the thalamus characterized by microglial activation and neuronal loss. Neuronal loss was restricted to areas of microglial infiltration. Treatment with OPN significantly decreased neurodegeneration, inflammation and microglial proliferation. Microglia displayed morphological signs of activation without expressing markers of M1 or M2 polarization. D-CIS-[F]FPRO-uptake mirrored attenuated degeneration in OPN-treated animals. Notably, [H]thymidine and BrdU-staining revealed increased stem cell proliferation after treatment with OPN. The data suggest that OPN is able to ameliorate secondary neurodegeneration in thalamic nuclei. These effects can be visualized by radiotracers D-CIS-[F]FPRO and [H]thymidine, opening new vistas for translational studies. Graphical Abstract Intracerebroventricular injection of osteopontin attenuates thalamic degeneration after cortical ischemia (pink area). Disruption of thalamocortical connections (blue) and degeneration of thalamic nuclei (encircled) leads to microglia activation. Osteopontin protects from both neurodegeneration and microglia activation as assessed by histological analysis and autoradiograpic studies.
皮质性脑缺血引起神经炎症以及远隔部位的继发性神经元变性。影响与皮质区相连的丘脑核的局部独特和特定的继发性神经退行性变突出了这些过程。骨桥蛋白 (OPN) 是一种细胞因子样糖蛋白，在脑缺血后大量分泌，并发挥各种免疫调节功能。我们在此研究了 OPN 在继发性丘脑变性中的潜在保护作用。我们使雄性 Wistar 大鼠经受光血栓形成，然后将 OPN 或安慰剂脑室内注射。免疫组织化学和荧光染色用于检测神经元变性和小胶质细胞激活的程度。使用可用于人类体内正电子发射断层扫描研究的放射性示踪剂，即 CIS-4-[F]氟-D-脯氨酸 (D-cis-[F]FPRO) 和 [6-H]胸腺嘧啶 ([H]thymidine)，进行离体放射性自显影，分别证实变性和增殖。我们发现丘脑的继发性神经退行性变特征为小胶质细胞激活和神经元丢失。神经元丢失仅限于小胶质细胞浸润的区域。OPN 治疗显著降低了神经退行性变、炎症和小胶质细胞增殖。小胶质细胞显示出激活的形态学迹象，但不表达 M1 或 M2 极化的标志物。D-CIS-[F]FPRO 摄取反映了 OPN 治疗动物中变性的减轻。值得注意的是，[H]thymidine 和 BrdU 染色显示 OPN 治疗后干细胞增殖增加。数据表明，OPN 能够改善皮质性脑缺血后丘脑核的继发性神经退行性变。这些作用可以通过放射性示踪剂 D-CIS-[F]FPRO 和 [H]thymidine 进行可视化，为转化研究开辟了新的视野。
