Abstract
The underlying mechanisms of cerebral ischemia/reperfusion (I/R) injury are unclear. Within this study, we aimed to explore whether p53 inhibition exerts protective effects via the p53/PRAS40/mTOR pathway after stroke and its potential mechanism. Both an in vitro oxygen-glucose deprivation (OGD) model with a primary neuronal culture and in vivo stroke models (dMCAO or MCAO) were used. We found that the infarction size, neuronal apoptosis, and autophagy were less severe in p53 KO mice and p53 KO neurons after cerebral I/R or OGD/R injury. By activating the mTOR pathway, p53 knockdown alleviated cerebral I/R injury both in vitro and in vivo. When PRAS40 was knocked out, the regulatory effects of p53 overexpression or knockdown against stroke disappeared. PRAS40 knockdown could inhibit the activities of the mTOR pathway; moreover, neuronal autophagy and apoptosis were exacerbated by PRAS40 knockdown. To sum up, in this study, we showed p53 inhibition protects against neuronal I/R injury after stroke via the p53/PRAS40/mTOR pathway, which is a novel and pivotal cerebral ischemic injury signaling pathway. The induction of neuronal autophagy and apoptosis by the p53/PRAS40/mTOR pathway may be the potential mechanism of this protective effect.
Highlights
Cerebral ischemia/reperfusion (I/R) injury is a pathophysiological process that impairs neuronal survival after stroke [1], but its underlying mechanisms are still not clear. p53, a pivotal tumor suppressor, is thought to exacerbate brain I/ R injury [2], some controversy remains
The results showed that p-mammalian target of rapamycin (mTOR) and p-S6K levels were decreased by p53-overexpressing group (p53 OE) (Figure 1(c)) but increased by p53 KD (Figure 1(d)) after oxygen and glucose deprivation (OGD)/R injury
This study provides the first evidence that inhibition of p53 alleviates neuronal I/R injury both in vivo and in vitro via the pivotal p53/PRAS40/mTOR pathway
Summary
Cerebral ischemia/reperfusion (I/R) injury is a pathophysiological process that impairs neuronal survival after stroke [1], but its underlying mechanisms are still not clear. p53, a pivotal tumor suppressor, is thought to exacerbate brain I/ R injury [2], some controversy remains. Cerebral ischemia/reperfusion (I/R) injury is a pathophysiological process that impairs neuronal survival after stroke [1], but its underlying mechanisms are still not clear. We found that inhibition of p53 had protective effects against neuronal oxygen and glucose deprivation (OGD) injury in vitro by activating the mammalian target of rapamycin (mTOR) pathway [3]. The mTOR pathway participates in a variety of physiological processes, including cell metabolism, growth, differentiation, development, and cell survival [4]. It is involved in protection against cerebral ischemia [5]. We demonstrated that the activation of mTOR alleviated stroke-related neuronal injury [6] [7]. The specific regulatory mechanisms linking the p53 and mTOR pathways need to be further explored [8]
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