p53 Inhibition Protects against Neuronal Ischemia/Reperfusion Injury by the p53/PRAS40/mTOR Pathway

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.

The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats

“…As is known, the mechanisms responsible for cerebral ischemia-reperfusion injury are relatively complex, and the related theories mainly include mitochondrial energy metabolism dysfunction, intracellular Ca 2+ Cheng et al, 2003). Besides, p53-de ciency or pharmacological suppression of p53 can lessen neuronal injury and promote functional recovery after cerebral ischemia (Leker et al, 2004;Zhao et al, 2021). So Caspase-3 and p53 are known as the executing molecules that exert an apoptotic function in various apoptotic pathways (Guzenko et al, 2023;Liu et al, 2019;Broughton et al, 2009).…”

The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats

“…As is known, the mechanisms responsible for cerebral ischemia-reperfusion injury are relatively complex, and the related theories mainly include mitochondrial energy metabolism dysfunction, intracellular Ca 2+ Cheng et al, 2003). Besides, p53-de ciency or pharmacological suppression of p53 can lessen neuronal injury and promote functional recovery after cerebral ischemia (Leker et al, 2004;Zhao et al, 2021). So Caspase-3 and p53 are known as the executing molecules that exert an apoptotic function in various apoptotic pathways (Guzenko et al, 2023;Liu et al, 2019;Broughton et al, 2009).…”

P53 protein and the diseases in central nervous system

“…The over-expression of pPRAS40 can reduce brain ischemia/reperfusion (I/R) damage and autophagy by activating mTOR. Not only that, studies have suggested that there is a negative feedback relationship between P53 and PRAS40, and P53 can be inhibited by its downstream factor PRAS40 (Havel et al, 2015;Zhao et al, 2021). In three groups of mice experiments: P53 KO mice (P53−/−), heterozygous (P53+/−) mice, and WT mice (P53+/+), the results showed that both P53 KO and heterozygous groups had an improved neurological function and reduced area of cerebral infarction, and P53 KO group showed a better protective effect (Havel et al, 2015).…”