Department of Neurosurgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
Department of Neurosurgery, Xinhua hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Int Immunopharmacol. 2023 Dec;125(Pt A):111108. doi: 10.1016/j.intimp.2023.111108. Epub 2023 Oct 25.
Currently, there are no effective therapeutic targets for the treatment of chronic cerebral hypoperfusion(CCH)-induced cerebral ischemic injury. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are discovered as the inducers of neurogenesis and angiogenesis. We previously made a nanofiber membrane (NFM), maintaining a long-term release of VEGF and bFGF up to 35 days, which might make VEGF and bFGF NFM as the potential protective agents against cerebral ischemic insult. In this study, the effects of VEGF and bFGF delivered by NFM into brain were investigated as well as their underlying mechanismsin a rat model of CCH. VEGF + bFGF NFM application increased the expressions of tight junction proteins, maintained BBB integrity, and alleviated vasogenic cerebral edema. Furthermore, VEGF + bFGF NFM sticking enhanced angiogenesis and elevated CBF. Besides, VEGF + bFGF NFM treatment inhibited neuronal apoptosis and decreased neuronal loss. Moreover, roofing of VEGF + bFGF NFM attenuated microglial activation and blocked the launch of NLRP3/caspase-1/IL-1β pathway. In addition, VEGF + bFGF NFM administration prevented disruption to the pre/postsynaptic membranes and loss of myelin sheath, relieving synaptic injury and demyelination. Oligodendrogenesis, neurogenesis and PI3K/AKT/mTOR pathway were involved in the treatment of VEGF + bFGF NFM against CCH-induced neuronal injury and hypomyelination. These findings supported that VEGF + bFGF NFM application constitutes a neuroprotective strategy for the treatment of CCH, which may be worth further clinical translational research as a novel neuroprotective approach, benifiting indirect surgical revascularization.
目前，针对慢性脑低灌注（CCH）诱导的脑缺血损伤，尚无有效的治疗靶点。血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）被发现可诱导神经发生和血管生成。我们之前制作了一种纳米纤维膜（NFM），可将 VEGF 和 bFGF 的释放时间延长至 35 天，这使得 VEGF 和 bFGF NFM 成为潜在的脑缺血损伤保护剂。在这项研究中，我们研究了 NFM 向大脑中递送 VEGF 和 bFGF 的效果及其在 CCH 大鼠模型中的作用机制。VEGF+bFGF NFM 的应用增加了紧密连接蛋白的表达，维持了 BBB 的完整性，并减轻了血管源性脑水肿。此外，VEGF+bFGF NFM 的黏附促进了血管生成并提高了 CBF。此外，VEGF+bFGF NFM 处理抑制了神经元凋亡并减少了神经元的丢失。此外，VEGF+bFGF NFM 的覆盖减轻了小胶质细胞的激活并阻止了 NLRP3/caspase-1/IL-1β通路的启动。此外，VEGF+bFGF NFM 给药防止了突触前/后膜的破坏和髓鞘的丢失，缓解了突触损伤和脱髓鞘。少突胶质细胞发生、神经发生和 PI3K/AKT/mTOR 通路参与了 VEGF+bFGF NFM 治疗 CCH 诱导的神经元损伤和脱髓鞘。这些发现支持了 VEGF+bFGF NFM 的应用构成了一种治疗 CCH 的神经保护策略，这可能值得进一步的临床转化研究，作为一种新的神经保护方法，有益于间接的血管重建手术。
