Department of Physiology, Loma Linda University School of Medicine, Risley Hall, Room 223, Loma Linda, CA 92354, USA.
Department of Physiology, Loma Linda University School of Medicine, Risley Hall, Room 223, Loma Linda, CA 92354, USA.
Exp Neurol. 2019 Feb;312:72-81. doi: 10.1016/j.expneurol.2018.11.009. Epub 2018 Nov 30.
Disruption of the blood-brain barrier results in the formation of edema and contributes to the loss of neurological function following intracerebral hemorrhage (ICH). This study examined insulin-like growth factor-1 (IGF-1) as a treatment and its mechanism of action for protecting the blood-brain barrier after ICH in mice. 171 Male CD-1 mice were subjected to ICH via collagenase or autologous blood. A dose study for recombinant human IGF-1 (rhIGF-1) was performed. Brain water content and behavioral deficits were evaluated at 24 and 72 h after the surgery, and Evans blue extravasation and hemoglobin assay were conducted at 24 h. Western blotting was performed for the mechanism study and interventions were used targeting the IGF-1R/GSK3β/MEKK1 pathway. rhIGF-1 reduced edema and blood-brain barrier permeability, and improved neurobehavior outcomes. Western blots showed that rhIGF-1 reduced p-GSK3β and MEKK1 expression, thereby increasing occludin and claudin-5 expression. Inhibition and knockdown of IGF-1R reversed the therapeutic benefits of rhIGF-1. The findings within suggest that stimulation of the IGF-1R is a therapeutic target for ICH which may lead to improved neurofunctional and blood-brain barrier protection.
血脑屏障的破坏导致脑水肿的形成，并导致脑出血 (ICH) 后神经功能丧失。本研究探讨了胰岛素样生长因子-1 (IGF-1) 作为一种治疗方法及其在脑出血后保护血脑屏障的作用机制。171 只雄性 CD-1 小鼠通过胶原酶或自体血进行 ICH。进行了重组人 IGF-1 (rhIGF-1) 的剂量研究。术后 24 和 72 小时评估脑水含量和行为缺陷，并在 24 小时进行 Evans 蓝外渗和血红蛋白测定。进行了 Western blot 以进行机制研究，并针对 IGF-1R/GSK3β/MEKK1 通路进行了干预。rhIGF-1 可减轻脑水肿和血脑屏障通透性，并改善神经行为学结果。Western blot 显示 rhIGF-1 降低了 p-GSK3β 和 MEKK1 的表达，从而增加了 occludin 和 claudin-5 的表达。IGF-1R 的抑制和敲低逆转了 rhIGF-1 的治疗益处。研究结果表明，IGF-1R 的刺激是 ICH 的治疗靶点，可能导致神经功能和血脑屏障保护的改善。
