Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas, 08036 Barcelona, Spain.
3D Lab (Development, Differentiation and Degeneration), Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain.
Neuropharmacology. 2017 Sep 1;123:221-232. doi: 10.1016/j.neuropharm.2017.06.014. Epub 2017 Jun 15.
Brain inflammaging is increasingly considered as contributing to age-related cognitive loss and neurodegeneration. Despite intensive research in multiple models, no clinically effective pharmacological treatment has been found yet. Here, in the mouse model of brain senescence SAMP8, we tested the effects of proinsulin, a promising neuroprotective agent that was previously proven to be effective in mouse models of retinal neurodegeneration. Proinsulin is the precursor of the hormone insulin but also upholds developmental physiological effects, particularly as a survival factor for neural cells. Adeno-associated viral vectors of serotype 1 bearing the human proinsulin gene were administered intramuscularly to obtain a sustained release of proinsulin into the blood stream, which was able to reach the target area of the hippocampus. SAMP8 mice and the control strain SAMR1 were treated at 1 month of age. At 6 months, behavioral testing exhibited cognitive loss in SAMP8 mice treated with the null vector. Remarkably, the cognitive performance achieved in spatial and recognition tasks by SAMP8 mice treated with proinsulin was similar to that of SAMR1 mice. In the hippocampus, proinsulin induced the activation of neuroprotective pathways and the downstream signaling cascade, leading to the decrease of neuroinflammatory markers. Furthermore, the decrease of astrocyte reactivity was a central effect, as demonstrated in the connectome network of changes induced by proinsulin. Therefore, the neuroprotective effects of human proinsulin unveil a new pharmacological potential therapy in the fight against cognitive loss in the elderly.
脑衰老被认为是导致与年龄相关的认知能力下降和神经退行性变的原因之一。尽管在多种模型中进行了深入研究，但尚未发现临床上有效的药物治疗方法。在这里，我们在 SAMP8 小鼠的脑衰老模型中测试了胰岛素原的效果，胰岛素原是一种有前途的神经保护剂，先前已被证明在视网膜神经退行性变的小鼠模型中有效。胰岛素原是激素胰岛素的前体，但也具有发育生理作用，特别是作为神经细胞的存活因子。携带人胰岛素原基因的血清型 1 腺相关病毒载体被肌肉内给药，以实现胰岛素原向血液中的持续释放，从而能够到达海马体的靶区。SAMP8 小鼠和对照品系 SAMR1 在 1 个月大时接受治疗。6 个月时，行为测试显示接受空载体治疗的 SAMP8 小鼠出现认知能力下降。值得注意的是，接受胰岛素原治疗的 SAMP8 小鼠在空间和识别任务中的认知表现与 SAMR1 小鼠相似。在海马体中，胰岛素原诱导了神经保护途径和下游信号级联的激活，导致神经炎症标志物减少。此外，星形胶质细胞反应性的降低是一个核心效应，正如胰岛素原诱导的连接组网络变化所证明的那样。因此，人胰岛素原的神经保护作用揭示了一种新的药理学治疗潜力，可以对抗老年人的认知能力下降。
