Protective mechanism of FoxO1 against early brain injury after subarachnoid hemorrhage by regulating autophagy

Abstract

Introduction: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. Methods:In this study, we constructed the SAH model. In experiment I, low dose (50 μl of 1 × 10 8 IU/ml) or high dose (50 μl of 1 × 10 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. Results:The experiment I showed that either low or high dose of ad-FoxO1 could significantly improve nerve function, reduce cerebral water content and reduce bloodbrain 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. Conclusions:The findings in this study was beneficial for identifying the novel therapeutic target for the treatment of SAH.

The Critical Role of Sirt1 in Subarachnoid Hemorrhages: Mechanism and Therapeutic Considerations

“…Emerging evidence has revealed that modulating autophagy protected against SAH-induced brain injury [ 117 ]. Our recent study found that Acetyl CoA synthase 2 improved neurological deficits, brain edema, and neuronal death, which are shown to be responsible for poor outcomes after a SAH by enhancing autophagy [ 63 ], consistent with the results of Hao et al [ 118 ]. The activation of autophagy may be a promising strategy in the treatment of SAHs.…”

Low-dose LPS alleviates early brain injury after SAH by modulating microglial M1/M2 polarization via USP19/FOXO1/IL-10/IL-10R1 signaling

“…Forkhead box protein O1 (FOXO1), a well-studied member of FOX family, acts as a transcription factor to modulate downstream targets involved in cell apoptosis, autophagy, cell cycle arrest, oxidative stress and immune regulation [ 17 ]. FOXO1 improves SAH-induced neurological function, brain edema, BBB leakage and inflammation by promoting autophagy in rat [ 18 ]. Intriguingly, low-dose LPS protects against ischemia/reperfusion (I/R)-induced neuronal apoptosis by increasing FOXO1 and phosphorylated FOXO1 (p-FOXO1) [ 19 ].…”

Inhibition of Panx1 reduces neuroinflammatory response and alleviates brain damage in septic mice

“…The effectiveness of simple anti infection interventions is significant. Early excessive inflammatory response and late immunosuppressive state are the pathological and physiological characteristics of sepsis, and immunotherapy for sepsis has become a current research hotspot [2]. A certain amount of researches [3][4][5] has shown that reducing the activation of the NLRP3/Caspase-1 pathway can significantly improve sepsis induced neuroinflammation and alleviate brain damage in sepsis.…”