Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Im Neuenheimer Feld (INF) 366, 69120 Heidelberg, Germany.
Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364, 69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2020 Apr 14;117(15):8616-8623. doi: 10.1073/pnas.2001563117. Epub 2020 Mar 30.
In the adult brain, vascular endothelial growth factor D (VEGFD) is required for structural integrity of dendrites and cognitive abilities. Alterations of dendritic architectures are hallmarks of many neurologic disorders, including stroke-induced damage caused by toxic extrasynaptic NMDA receptor (eNMDAR) signaling. Here we show that stimulation of eNMDARs causes a rapid shutoff of expression, leading to a dramatic loss of dendritic structures. Using the mouse middle cerebral artery occlusion (MCAO) stroke model, we have established the therapeutic potential of recombinant mouse VEGFD delivered intraventricularly to preserve dendritic architecture, reduce stroke-induced brain damage, and facilitate functional recovery. An easy-to-use therapeutic intervention for stroke was developed that uses a new class of VEGFD-derived peptide mimetics and postinjury nose-to-brain delivery.
在成人大脑中，血管内皮生长因子 D（VEGFD）对于树突的结构完整性和认知能力是必需的。树突结构的改变是许多神经疾病的标志，包括由毒性突触外 NMDA 受体（eNMDAR）信号引起的中风损伤。在这里，我们表明，eNMDAR 的刺激会导致 表达的快速关闭，导致树突结构的显著丧失。我们使用小鼠大脑中动脉闭塞（MCAO）中风模型，已经证实了脑室内给予重组小鼠 VEGFD 的治疗潜力，以保护树突结构、减少中风引起的脑损伤并促进功能恢复。开发了一种易于使用的中风治疗干预措施，该措施使用了一类新的 VEGFD 衍生肽模拟物和损伤后鼻脑递送。
