Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P. R. China.
Henan Key Laboratory of Neurorestoratology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, P. R. China.
Brain Behav. 2021 Nov;11(11):e2376. doi: 10.1002/brb3.2376. Epub 2021 Oct 17.
Early brain injury (EBI) plays a key role in the devastating outcomes after subarachnoid hemorrhage (SAH). Autophagy and apoptosis may share a common molecular inducer that regulates the process of cell death. FoxO1, as a key regulator of neuronal autophagy which is involved in apoptosis, has not been reported in SAH rats. This work was to investigate the protective and anti-inflammatory effects of FoxO1 on EBI after SAH by regulating autophagy.
In this study, we constructed the SAH model. In experiment I, low dose (50 μl of 1 × 10 IU/ml) or high dose (50 μl of 1 × 10 IU/ml) of FoxO1 gene overexpressed adenovirus vector was injected into the lateral ventricle of rats before SAH. In experiment II, we reported the effect of FoxO1 overexpress on nerve function recovery, oedema, BBB leakage, neuronal death in rats after SAH through autophagy regulation. Post-SAH evaluation included neurological function score, brain water content, evans blue exosmosis, pathological changes, inflammatory response and apoptosis.
The experiment I showed that either low or high dose of ad-FoxO1 could significantly improve nerve function, reduce cerebral water content and reduce blood-brain barrier (BBB) destruction in rats, indicating that ad-FoxO1 had a protective effect on brain injury in rats EBI after SAH. In addition, ad-FoxO1 promoted autophagy in rat hippocampal tissue, as evidenced by accumulation of LC3II/I and Beclin-1 and degradation of p62. Furthermore, ad-FoxO1 inhibited the inflammatory response and apoptosis of rat hippocampal neurons after SAH. The experiment II showed that both ad-FoxO1 and rapamycin attenuated the injury of nerve function in rats after SAH, and this synergistic effect further reduced cerebral edema and evansblue extravasation, decreased hippocampus neuronal cell apoptosis, and declined inflammatory response. However, this was contrary to the results of chloroquine. These findings suggested that FoxO1 regulated the neural function of EBI after SAH through the autophagy pathway.
The findings in this study was beneficial for identifying the novel therapeutic target for the treatment of SAH.
蛛网膜下腔出血 (SAH) 后早期脑损伤 (EBI) 起着至关重要的作用。自噬和细胞凋亡可能具有调节细胞死亡过程的共同分子诱导剂。FoxO1 作为参与细胞凋亡的神经元自噬的关键调节剂，在 SAH 大鼠中尚未见报道。本研究旨在通过调节自噬，探讨 FoxO1 对 SAH 后 EBI 的保护和抗炎作用。
在这项研究中，我们构建了 SAH 模型。在实验 I 中，在 SAH 前将低剂量（50 μl 1×10 IU/ml）或高剂量（50 μl 1×10 IU/ml）FoxO1 基因过表达腺病毒载体注入大鼠侧脑室。在实验 II 中，我们通过调节自噬报告了 FoxO1 过表达对 SAH 后大鼠神经功能恢复、脑水肿、BBB 渗漏、神经元死亡的影响。SAH 后评估包括神经功能评分、脑水含量、伊文思蓝渗出、病理变化、炎症反应和细胞凋亡。
实验 I 表明，低剂量或高剂量的 ad-FoxO1 均可显著改善大鼠神经功能，降低脑含水量，减轻血脑屏障（BBB）破坏，表明 ad-FoxO1 对大鼠 SAH 后 EBI 具有保护作用。此外，ad-FoxO1 促进了大鼠海马组织中的自噬，表现为 LC3II/I 和 Beclin-1 的积累和 p62 的降解。此外，ad-FoxO1 抑制了大鼠海马神经元 SAH 后的炎症反应和细胞凋亡。实验 II 表明，ad-FoxO1 和雷帕霉素均能减轻大鼠 SAH 后神经功能的损伤，这种协同作用进一步降低了脑水肿和伊文思蓝外渗，减少了海马神经元细胞凋亡，降低了炎症反应。然而，这与氯喹的结果相反。这些发现表明，FoxO1 通过自噬途径调节 SAH 后神经功能。
本研究的结果有助于确定治疗 SAH 的新治疗靶点。
