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

• Published in: Frontiers in aging neuroscience Vol. 12; p. 587403
• Main Authors: Li, Wenxian, Wei, Di, Zhu, Zheng, Xie, Xiaomei, Zhan, Shuqin, Zhang, Ru, Zhang, Guilian, Huang, Li'an
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 13.01.2021; Frontiers Media S.A
• Subjects: Aging; Apoptosis; Binding sites; Carotid artery; Cerebral blood flow; chronic cerebral hypoperfusion; CNTF signaling; Cognitive ability; Dl-3-n-butylphthalide; FDA approval; Glucose; Hippocampus; Ischemia; Janus kinase 2; Laboratory animals; Mimicry; Neurodegeneration; Neurological diseases; Neuromodulation; neuronal death; Neuroprotection; Neuroscience; Oxygen; Pharmaceutical industry; Reperfusion; Rodents; Seeds; Signal transduction; Stat3 protein; vascular cognitive impairment; China; vascular cognitive impairment; Dl-3-n-butylphthalide; CNTF signaling; chronic cerebral hypoperfusion; neuronal death
• DOI: 10.3389/fnagi.2020.587403
• ISSN: 1663-4365

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 , 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 . 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 or OGD/R . 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 . Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.