Dept. of Medical Biology, International School of Medicine, University of Health Sciences Turkey, Istanbul, Turkey.; Dept. of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey.; Dept. of Medical Biology, School of Medicine, Bezmialem Vakif University, Istanbul, Turkey.
Research Institute for Health Sciences and Technologies (SABITA), Regenerative and Restorative Medicine Research Center (REMER), Istanbul Medipol University, Istanbul, Turkey; Dept. of Physiology, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
Exp Neurol. 2020 Sep;331:113364. doi: 10.1016/j.expneurol.2020.113364. Epub 2020 May 23.
Owing to its potent longterm neuroprotective and neurorestorative properties, glial cell line-derived neurotrophic factor (GDNF) is currently studied in neurodegenerative disease clinical trials. However, little is known about the longterm effect of GDNF on neurological recovery, brain remodeling and neuroplasticity in the post-acute phase of ischemic stroke. In a comprehensive set of experiments, we examined the effects of lentiviral GDNF administration after ischemic stroke. GDNF reduced neurological deficits, neuronal injury, blood-brain barrier permeability in the acute phase in mice. As compared with control, enhanced motor-coordination and spontaneous locomotor activity were noted in GDNF-treated mice, which were associated with increased microvascular remodeling, increased neurogenesis and reduced glial scar formation in the peri-infarct tissue. We observed reduced brain atrophy and increased plasticity of contralesional pyramidal tract axons that crossed the midline in order to innervate denervated neurons in the ipsilesional red and facial nuclei. Contralesional axonal plasticity by GDNF was associated with decreased abundance of the axonal growth inhibitors brevican and versican in contralesional and ipsilesional brain tissue, reduced abundance of the growth repulsive guidance molecule ephrin b1 in contralesional brain tissue, increased abundance of the midline growth repulsive protein Slit1 in contralesional brain tissue and reduced abundance of Slit1's receptor Robo2 in ipsilesional brain tissue. These data indicate that GDNF potently induces longterm neurological recovery, peri-infarct brain remodeling and contralesional neuroplasticity, which are associated with the fine-tuned regulation of axonal growth inhibitors and guidance molecules that facilitate the growth of contralesional corticofugal axons in the direction to the ipsilesional hemisphere.
胶质细胞源性神经营养因子（GDNF）因其强大的长期神经保护和神经修复特性，目前正在进行神经退行性疾病的临床试验。然而，对于 GDNF 在缺血性中风后急性期对神经恢复、大脑重塑和神经可塑性的长期影响知之甚少。在一整套实验中，我们研究了缺血性中风后给予慢病毒 GDNF 的效果。GDNF 减少了急性阶段小鼠的神经功能缺损、神经元损伤和血脑屏障通透性。与对照组相比，GDNF 治疗的小鼠运动协调能力和自发运动活性增强，与梗死周边组织中微血管重塑增加、神经发生增加和神经胶质瘢痕形成减少有关。我们观察到，与对照组相比，大脑萎缩减少，对侧皮质锥体束轴突穿过中线的可塑性增加，以支配病变侧红核和面神经核中的去神经神经元。GDNF 通过对侧轴突可塑性与对侧和病变侧脑组织中轴突生长抑制剂 brevican 和 versican 的丰度降低、对侧脑组织中生长排斥性导向分子 ephrin b1 的丰度降低、对侧脑组织中中线生长排斥性蛋白 Slit1 的丰度增加以及病变侧脑组织中 Slit1 的受体 Robo2 的丰度降低有关。这些数据表明，GDNF 能强力诱导长期神经恢复、梗死周边大脑重塑和对侧神经可塑性，这与轴突生长抑制剂和导向分子的精细调节有关，促进了对侧皮质传出轴突向病变侧半球生长。
