Ginsenoside Reduces Cognitive Impairment During Chronic Cerebral Hypoperfusion Through Brain-Derived Neurotrophic Factor Regulated by Epigenetic Modulation

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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Therapeutic Benefits of Methylene Blue on Cognitive Impairment during Chronic Cerebral Hypoperfusion

Journal of Alzheimer s Disease ◽

10.3233/jad-141527 ◽

2014 ◽

Vol 42 (s4) ◽

pp. S525-S535 ◽

Cited By ~ 14

Author(s):

Allison Auchter ◽

Justin Williams ◽

Bryan Barksdale ◽

Marie H. Monfils ◽

Francisco Gonzalez-Lima

Keyword(s):

Methylene Blue ◽

Cognitive Impairment ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Therapeutic Benefits

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Brain-derived neurotrophic factor Val66Met polymorphism is associated with mild cognitive impairment in elderly patients with type 2 diabetes: a case-controlled study

Aging Clinical and Experimental Research ◽

10.1007/s40520-020-01687-w ◽

2020 ◽

Author(s):

Jia Liu ◽

Wei Yang ◽

Hongyu Luo ◽

Yixin Ma ◽

Huan Zhao ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Elderly Patients ◽

Neurotrophic Factor ◽

Brain Derived Neurotrophic Factor ◽

Controlled Study ◽

Val66met Polymorphism

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Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Neural Plasticity ◽

10.1155/2019/2158285 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Zhao-Hui Yao ◽

Xiao-li Yao ◽

Shao-feng Zhang ◽

Ji-chang Hu ◽

Yong Zhang

Keyword(s):

Cognitive Impairment ◽

Synaptic Plasticity ◽

Learning And Memory ◽

Spatial Learning ◽

Long Term Potentiation ◽

Chronic Cerebral Hypoperfusion ◽

Synaptic Proteins ◽

Cerebral Hypoperfusion ◽

Spatial Learning And Memory ◽

Pathophysiological Mechanism

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

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