Artesunate promotes the proliferation of neural stem/progenitor cells and alleviates Ischemia-reperfusion Injury through PI3K/Akt/FOXO-3a/p27kip1 signaling pathway

Abstract

Stroke is one of the leading causes of death worldwide that also result in long-term disability. Endogenous neural stem/progenitor cells (NSPCs) within subventricular (SVZ) and dentate gyrus (DG) zone, stimulated by cerebral infarction, can promote neural function recovery. However, the proliferation of eNSPCs triggered by ischemia is not enough to induce neural repair, which may contribute to the permanent disability in stroke patients. In this study, our results showed that following the treatment with artesunate (ART, 150 mg/kg), the functional recovery was significantly improved, the infarct volume was notably reduced, and the expression of Nestin, a proliferation marker of NSPCs in the infarcted cortex, was also increased. Additionally, the proliferative activity of NSPCs with or without oxygen-glucose deprivation/reperfusion was significantly promoted by ART treatment, and the therapeutic concentration was 0.8 μmol/L (without OGD/R) or 0.4 μmol/L (with OGD/R) in the in vitro model. Furthermore, the effects of ART can be abolished by the treatment of PI3K inhibitor wortmannin. The expression levels of related molecules in PI3K/Akt/FOXO-3a/p27 kip1 signaling pathway (p-AKT, p-FOXO-3a, p27 kip1) were examined using western blotting. The results suggested ART could inhibit the transcriptional function of FOXO-3a by inducing its phosphorylation, subsequently downregulating p27 kip1 and enhancing neural stem cell proliferation in the infarcted cortex via PI3K/AKT signaling, further alleviating ischemia-reperfusion injury after ischemic stroke.

Artesunate Provides Neuroprotection against Cerebral Ischemia–Reperfusion Injury <i>via</i> the TLR-4/NF-κB Pathway in Rats

“…23) Previous studies have shown that ART can alleviate I/R injury after a stroke. 16,17) These findings are consistent with our results. Shao et al used two ART groups (30 mg/kg and 60 mg/kg) and both showed neuroprotective effects.…”

“…16) Zhang et al used three ART groups (50 mg/kg, 150 mg/kg, and 250 mg/kg) and showed that 150 mg/kg was the optimal ART dosage. 17) We designed four ART groups (20 mg/kg, 40 mg/kg, 80 mg/kg, and 160 mg/kg) and all showed neuroprotective effect vs. the vehicle group. Among them, 80 mg/kg was the optimal ART dosage for the rats.…”

“…16) Zhang et al found that ART could alleviate I/R injury by enhancing neural stem cell proliferation. 17) However, the neuroprotective mechanism of ART for brain I/R injury remains unclear. Here, we have provided new evidence about the mechanism.…”

Suppressive effects of plumbagin on the growth of human bladder cancer cells via PI3K/AKT/mTOR signaling pathways and EMT

“…Our results showed that PL significantly reduced the expression of PI3K/AKT/mTOR at the protein level, therefore, we believe that PL may exert its cycle arrest and induce cell apoptosis through the PI3K/AKT/mTOR signaling pathway. AKT can promote the phosphorylation of MDM2 to inhibit the degradation of p53 [ 44 ], and AKT can directly inhibit the phosphorylation of p21 and p27 to achieve the purpose of cell cycle arrest [ 45 , 46 ]. In addition, AKT inhibits the phosphorylation of GSK-3β [ 47 ], GSK-3β further induced apoptosis [ 48 ], several researchers have revealed that PL shows its cell cycle arrest and apoptosis by inhibiting PI3K/AKT/mTOR in other cell lines [ 49 – 51 ].…”

Stem Cell-Based Therapy for Experimental Ischemic Stroke: A Preclinical Systematic Review

“…Furthermore, whether we can promote the proliferation of endogenous stem cells through some exogenous interventions may also be a novel therapeutic approach. For example, Zhang et al (2020) showed that treatment with artesunate promoted the proliferation of NSPCs via some molecular mechanisms, subsequently reducing the infracted brain volume and alleviating motor function impairment caused by MCAO. Zhuang et al (2012) had undertaken a study to examine the promotive effect of salvianolic acid B (Sal B) on NSPC proliferation and neurogenesis.…”