mTOR/autophagy pathway in the hippocampus of rats suffering intermittent hypoxia preconditioning and global cerebral ischemia-reperfusion

Abstract

We explored the role of mTOR/autophagy pathway in the aggravation of cerebral ischemia-reperfusion nerve injury caused by intermittent hypoxia. Eighty male wistar rats were divided into four groups by the random number method: sham operation group (SO group, n=20), cerebral ischemia-reperfusion group (I/R group, n=20), intermittent hypoxia and cerebral ischemia-reperfusion group (IH+I/R group, n=20), intermittent hypoxia and cerebral ischemia-reperfusion group plus mTOR inhibitor group (inhibitor group, n=20). The results showed that compared with the SO group, HE staining showed structural damage of neurons at each time point, the immunohistochemical assay showed an increasing number of mTOR and beclin1 immune-positive cells (P<0.05) and RT-PCR showed enhanced expression of mTOR and beclin1 protein in the I/R group (P<0.05). Compared with the I/R group, HE staining showed exacerbating structural damage of neurons at each time point, the immunohistochemical assay showed an increasing number of mTOR and beclin1 immune-positive cells (P<0.05) and RT-PCR showed enhanced expression of mTOR and beclin1 protein in the IH+I/R group (P<0.05). Compared with the IH+I/R group, HE staining showed remissive structural damage of neurons at each time point, the immunohistochemical assay showed a decreasing number of mTOR immune-positive cells and a rising number of beclin1immune-positive cells (P<0.05) and RT-PCR showed weakened expression of mTOR protein and enhanced expression of beclin1 protein in the inhibitor group (P<0.05). Thence, the present study indicated that intermittent hypoxia preconditioning can aggravate the nerve injury of the global cerebral ischemia-reperfusion model, and the mechanism is associated with the activation of mTOR/autophagy pathway.

Germacrone protects against oxygen-glucose deprivation/reperfusion injury by inhibiting autophagy processes in PC12 cells

“…Moderate autophagy induced by mild hypoxia can enhance the ability of nerve cells to resist changes in the external environment, thus improving the survival rate of cells [5]. However, excessive activation of autophagy caused by severe hypoxia can lead to injury and apoptosis of nerve cells [6].…”

Role of HIF-1a in regulating autophagic cell survival during cerebral ischemia reperfusion in rats

“…The previous studies had mainly focused on the study of brain cell apoptosis, while the effects of HIF-1a on autophagy remain unexplored. Indeed, recent studies have revealed the importance of cell autophagy in the protection of the brain cells [ 3 , 15 – 21 ]. However, a role of HIF-1a in the regulation of brain cell autophagy after IR has not been studied.…”

“…Cerebral ischemia reperfusion (IR) causes cerebral injury and brain dysfunction due to oxidative damage and apoptotic cell death [ 2 , 3 ]. Although it is critical to provide reperfusion to the ischemic tissue at earliest stage, the outcome may not be ideal due to the presence of free oxygen radicals in IR [ 4 ].…”

“…Among all these autophagy-associated proteins, autophagy-related protein 6 (ATG6, or Beclin-1) appears to be a critical one, which is a component of a class III PI3-K-containing complex [ 14 ]. Recent studies have demonstrated a critical role of autophagy in the brain cell survival during IR [ 3 , 15 – 21 ]. Nevertheless, regulation of brain cell autophagy by HIF-1a in IR has not been extensively reported.…”