Neuroprotective Effects of Cerebral Ischemic Preconditioning in a Rat Middle Cerebral Artery Occlusion Model: The Role of the Notch Signaling Pathway.

Li Chen,Rui Guo,Kuan Huang,Lifeng Wang,Qiong Jiang,Zhenghua Wu,Rong Wang,Weidong Liang

doi:10.1155/2018/8168720

Abstract

Cerebral ischemia-reperfusion (I/R) injury is a major problem worldwide. The Notch signaling pathway plays an important role in neural progenitor cell differentiation and in the inflammatory response after central nervous system injury. This study evaluated whether the neuroprotective effect of cerebral ischemic preconditioning (cIPC) is mediated by the preactivation of the Notch signaling pathway. A rat middle cerebral artery occlusion/reperfusion (MCAO/R) model and glucose deprivation/reoxygenation (OGD/R) cell model were constructed to detect the neuroprotective effects of cIPC. In in vivo experiments, cIPC reduces the neurological functional deficit, cerebral infarction, and cellular apoptosis in the hippocampus induced by middle cerebral artery occlusion/reperfusion (MCAO/R), thus indicating that cIPC can improve neurologic function. Moreover, cIPC can reveal the expression peak of Jagged1, Notch1, NICD, and Hes1 protein, thereby indicating that cIPC can preactivate Notch signaling. However, cIPC-induced improvements in neurologic function are compromised by the γ-secretase inhibitor N-(N-(3,5-difluorophenacetyl)-1-alanyl)-S-phenylglycine t-butyl ester (DAPT). In in vitro experiments, OGD preconditioning (OGDPC) can clearly upregulate Notch1 expression in the OGD/R-treated neuron and neural stem cell. Notch1 pre-overexpression can decrease neuron death and apoptosis under OGD/R treatment. Notch1 pre-overexpression can decrease the percentage of G1 stage cells and increase the percentage of S stage cells in OGD/R-treated neural stem cell. Furthermore, Notch1 pre-knockdown has the opposite effect on cell survival, apoptosis, and cycle in both OGD/R-treated neuron and neural stem cell. In conclusion, our results demonstrate that the neuroprotective effects of cIPC in a rat MCAO/R model are mediated by the preactivation of the Notch signaling pathway.

Highlights

Cerebral ischemia-reperfusion (I/R) injury is a major problem worldwide
The results of the neurological function testing showed that DAPT pretreatment could increase the neurological deficit score, which was decreased by cerebral ischemic preconditioning (cIPC) in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model (Figure 4(b))
Cerebral I/R injury induced by irreversible functional impairment and/or neuronal death is a controversial issue in the treatment of cerebral I/R injury-related diseases, such as stroke and cerebral trauma [1, 2]

Summary

Introduction

Cerebral I/R injury often causes irreversible brain damage that leads to functional impairment and/or neuronal death [1, 2] The treatment for this disorder remains palliative only. Notch signaling is evolutionarily conserved from Drosophila to humans It plays an important role in neural stem cell maintenance and neurogenesis in the embryonic brain and adult brain [8, 9]. A recent study showed that the neuroprotective effects of isoflurane preconditioning in a murine transient global cerebral I/R model are mediated by the preactivation of the Notch signaling pathway [12, 13]. Whether the Notch signaling pathway plays a role in the neuroprotective effects of cIPC remains unclear. Our hypothesis is that the neuroprotection of cIPC is mediated by the preactivation of the Notch signaling pathway

Materials and Methods

Results

Discussion