Artesunate promotes the proliferation of neural stem/progenitor cells and alleviates Ischemia-reperfusion Injury through PI3K/Akt/FOXO-3a/p27kip1 signaling pathway
Open Access
- 7 May 2020
- journal article
- research article
- Published by Impact Journals, LLC in Aging
- Vol. 12 (9), 8029-8048
- https://doi.org/10.18632/aging.103121
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 mu mol/L (without OGD/R) or 0.4 mu mol/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.Keywords
This publication has 42 references indexed in Scilit:
- FoxO is a critical regulator of stem cell maintenance in immortal HydraProceedings of the National Academy of Sciences of the United States of America, 2012
- FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expressionCell Death & Differentiation, 2011
- FoxO transcription factors; Regulation by AKT and 14-3-3 proteinsBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2011
- Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant QuestionsNeuron, 2011
- The Science of Stroke: Mechanisms in Search of TreatmentsNeuron, 2010
- The Ladder Rung Walking Task: A Scoring System and its Practical Application.Journal of Visualized Experiments, 2009
- A New Fork for Clinical Application: Targeting Forkhead Transcription Factors in CancerClinical Cancer Research, 2009
- p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cellsMolecular Cancer Therapeutics, 2007
- FoxOs Are Lineage-Restricted Redundant Tumor Suppressors and Regulate Endothelial Cell HomeostasisCell, 2007
- Posttranslational modifications of p27kip1 determine its binding specificity to different cyclins and cyclin-dependent kinases in vivoBlood, 2005