Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways.
Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways.
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DOI：
10.3389/fnagi.2020.587403
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发表时间：
2020
影响因子：
4.8
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Li W;Wei D;Zhu Z;Xie X;Zhan S;Zhang R;Zhang G;Huang L
慢性脑灌注不足（CCH）是认知功能障碍的重要原因之一，海马神经元死亡是其重要的病理机制。DL-3-正丁基苯酞（D3 NB）是从芹菜种子中分离得到的一种人工合成化合物，对某些神经系统疾病具有神经保护作用。然而，D3 NB在模拟血管性认知障碍的CCH模型中的保护机制仍有待探索。我们通过双侧颈总动脉闭塞（BCCAO）手术诱导大鼠CCH。将动物随机分为假手术组、CCH 4周组、CCH 8周组和相应的D3 NB治疗组。采用体外培养的原代海马神经元进行氧-糖剥夺/再灌注（OGD/R）模拟CCH。本研究旨在探讨D3 NB对慢性脑缺血后海马神经元死亡的影响及其分子机制。与假手术对照组相比，CCH组大鼠记忆力下降，海马神经元凋亡增加，并伴有CNTF/CNTFRα/JAK 2/STAT 3信号通路的抑制。D3 NB可明显减轻CCH大鼠的认知功能障碍，并减少BCCAO后海马神经元的凋亡。更重要的是，D3 NB逆转了CNTF/CNTFRα表达的抑制，激活了JAK 2/STAT 3通路。此外，JAK 2/STAT 3通路抑制剂AG 490在体外抵消了D3 NB的保护作用。结果提示，D3 NB可改善CCH后的认知功能，其神经保护作用可能与通过调节CNTF/CNTFRα/JAK 2/STAT 3信号通路减少海马神经元凋亡有关。D3 NB可能是治疗CCH引起的血管性认知障碍的一种有前途的治疗策略。
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.
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