Thousand and one kinase 1 protects MCAO-induced cerebral ischemic stroke in rats by decreasing apoptosis and pro-inflammatory factors.

Jiahui Li,Zhijie Liu,Liling Wang,Yulin Wang,Haiyan Xu

doi:10.1042/bsr20190749

Abstract

Background: Birth hypoxia causes neonatal mortality and morbidity. Hypoxia/ischemia can facilitate brain damage, causing various kinds of diseases, such as ischemic stroke. It is necessary to understand the potential underlying mechanisms of ischemic stroke. Previous studies revealed the involvement of thousand and one kinase 1 (TAOK1) in many cellular processes. Methods: Herein, middle cerebral artery (MCA) occlusion (MCAO) was performed in rats to establish ischemic stroke in the animal model, and cortical neural stem cells from rats were treated with oxygen-glucose deprivation (OGD) to induce ischemic stroke cell model. The animal model of ischemic stroke was validated by Bederson and Zea-Longa neurological deficit scores and rotarod test. TAOK1 expression was examined by quantitative real-time PCR (qRT-PCR), Western blot, and immunofluorescent staining both in vivo and in vitro. Result: Compared with sham animals, the MCAO rats showed a significant increase in the neurological scores, and obvious motor behavioral deficits. Meanwhile, there was increased apoptosis and inflammatory response in the model group. TAOK1 overexpression reversed the OGD-induced cell injury, while TAOK1 knockdown exhibited the opposing effects. On the mechanism, the OGD-induced suppression of PI3K/AKT, and activation of mitogen-activated protein kinase (MAPK) signaling pathways were abolished by TAOK1 overexpression, and aggravated by TAOK1 knockdown in vitro. Moreover, we proved that the inhibitory effect of TAOK1 on OGD-induced apoptosis was dependent on the intracellular kinase activity. Conclusion: TAOK1 protected MCAO-induced cerebral ischemic stroke by decreasing the pro-inflammatory factors and apoptosis via PI3K/AKT and MAPK signaling pathways.

Highlights

Hypoxic–ischemic encephalopathy (HIE) is a major cause of neonatal death, resulting in long-term neurological dysfunction
We found that thousand and one kinase 1 (TAOK1) and Nestin were highly expressed in the brain of MCA occlusion (MCAO) rats (Supplementary Figure S1A), the results revealed that TAOK1 and Nestin were widely distributed in in the subependymal ventricular zone (SVZ) of brain (Supplementary Figure S1)
We detected the expression of TAOK1 in oxygen-glucose deprivation (OGD)-treated neural stem cells, and the results suggested that TAOK1 mRNA and protein expression in OGD-treated neural stem cells were significantly decreased when compared with normal neural stem cells (***P

Summary

Introduction

Hypoxic–ischemic encephalopathy (HIE) is a major cause of neonatal death, resulting in long-term neurological dysfunction. Tissue plasminogen activator (tPA) is the only drug approved by the Food and Drug Administration (FDA) for ischemic stroke to date, and has limited effects due to its remarkably short therapeutic time window [8,9,10]. The OGD-induced suppression of PI3K/AKT, and activation of mitogen-activated protein kinase (MAPK) signaling pathways were abolished by TAOK1 overexpression, and aggravated by TAOK1 knockdown in vitro. Conclusion: TAOK1 protected MCAO-induced cerebral ischemic stroke by decreasing the pro-inflammatory factors and apoptosis via PI3K/AKT and MAPK signaling pathways

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