Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways.

Wenxian Li,Xiaomei Xie,Zheng Zhu,Li’An Huang,Di Wei,Guilian Zhang,Shuqin Zhan,Ru Zhang

doi:10.3389/fnagi.2020.587403

Abstract

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.

Highlights

Chronic cerebral hypoperfusion (CCH) is characterized by reduced cerebral blood flow (CBF), which is induced by cerebrovascular diseases (Han et al, 2020)
We explored the relationship between CNTF/CNTFRα/JAK2/STAT3 signaling pathways, which are the regulatory targets of D3NB, and hippocampal neuronal death during the CCH process
These results suggest that the spatial memory of CCH rats was impaired, and D3NB improved the spatial memory of CCH rats

Summary

Introduction

Chronic cerebral hypoperfusion (CCH) is characterized by reduced cerebral blood flow (CBF), which is induced by cerebrovascular diseases (Han et al, 2020). Studies have reported that the underlying pathophysiological mechanisms of CCH may contribute to the development of degenerative processes and cognitive decline that lead to vascular dementia (VD) and Alzheimer’s disease (AD; Duncombe et al, 2017; Li et al, 2019b). Neuronal death is a hallmark of cognitive disorders that are induced by CCH, especially at later stages (Chen et al, 2017; Li et al, 2019a,b). These changes can be accompanied by or lead to abnormal brain structure and function at later stages of CCH. Since the hippocampus plays a critical role in cognitive processes and the CA1 region in the hippocampus is highly vulnerable to ischemic injury (Wang et al, 2004), the molecular mechanisms underlying CCH in neuronal death in the hippocampus should be further investigated

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