Previous studies have shown that alterations in autophagy-related proteins exist extensively after traumatic brain injury (TBI). However, whether autophagy is enhanced or suppressed by TBI remains controversial. In our study, a controlled cortical impact was used to establish a model of moderate TBI in rats. We found that a significant increase in protein levels of LC3-II and SQSTM1 in the injured cortex group. However, there were no significant differences in protein levels of VPS34, Beclin-1, and phosphor-ULK1, which are the promoters of autophagy. Lysosome dysfunction after TBI might lead to autophagosome accumulation. In addition, the highly specific autophagy inhibitor SAR405 administration reduced TBI-induced apoptosis-related protein cleaved caspase-3 and cleaved caspase-9 levels in the ipsilateral cortex, as well as brain edema and neurological defects accessed by mNSS. Furthermore, chloroquine treatment reversed the beneficial effects of SAR405 by increasing the accumulation of autophagosomes. Finally, our data showed that autophagy inhibition by VPS34 gene knockout method attenuated cell death after TBI. Our findings indicate that impaired autophagosome degradation is involved in the pathological reaction after TBI, and the inhibition of autophagy contributes to attenuate neuronal cell death and functional defects.

先前的研究表明，自噬相关蛋白的改变在颅脑损伤（TBI）后广泛存在。但是，是否通过TBI增强或抑制自噬仍存在争议。在我们的研究中，可控的皮层撞击被用于建立大鼠中度TBI模型。我们发现受伤的皮层组中LC3-II和SQSTM1的蛋白质水平显着增加。但是，作为自噬的启动子的VPS34，Beclin-1和荧光素ULK1的蛋白质水平没有显着差异。TBI后的溶酶体功能障碍可能导致自噬体积累。此外，高度特异性的自噬抑制剂SAR405的使用降低了同侧皮质中TBI诱导的凋亡相关蛋白切割的caspase-3和caspase-9的水平，以及通过mNSS访问的脑水肿和神经系统缺损。此外，氯喹处理通过增加自噬体的积累逆转了SAR405的有益作用。最后，我们的数据表明，通过VPS34基因敲除方法的自噬抑制作用可减轻TBI后的细胞死亡。我们的研究结果表明受损的自噬体降解与TBI后的病理反应有关，自噬的抑制作用有助于减轻神经元细胞的死亡和功能缺陷。