scholarly journals Xi-Xian-Tong-Shuan capsule alleviates vascular cognitive impairment in chronic cerebral hypoperfusion rats by promoting white matter repair, reducing neuronal loss, and inhibiting the expression of pro-inflammatory factors

2022 ◽  
Vol 145 ◽  
pp. 112453
Author(s):  
Feng Yan ◽  
Yue Tian ◽  
Yuyou Huang ◽  
Qi Wang ◽  
Ping Liu ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Neuronal Loss ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Inflammatory Factors ◽  
White Matter Repair

scholarly journals Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

2017 ◽  
Vol 131 (19) ◽  
pp. 2451-2468 ◽  
Author(s):  
Jessica Duncombe ◽  
Akihiro Kitamura ◽  
Yoshiki Hase ◽  
Masafumi Ihara ◽  
Raj N. Kalaria ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Pathophysiological Mechanism ◽  
Rodent Models ◽  
Recent Refinement

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

scholarly journals Lessons from a Mouse Model Characterizing Features of Vascular Cognitive Impairment with White Matter Changes

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Masafumi Ihara ◽  
Hidekazu Tomimoto
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Mouse Model ◽  
The Elderly ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Demographic Shift ◽  
White Matter Changes ◽  
Blood Brain Barrier Disruption

With the demographic shift in age in advanced countries inexorably set to progress in the 21st century, dementia will become one of the most important health problems worldwide. Vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease and is frequently responsible for the cognitive decline of the elderly. It is characterized by cerebrovascular white matter changes; thus, in order to investigate the underlying mechanisms involved in white matter changes, a mouse model of chronic cerebral hypoperfusion has been developed, which involves the narrowing of the bilateral common carotid arteries with newly designed microcoils. The purpose of this paper is to provide a comprehensive summary of the achievements made with the model that shows good reproducibility of the white matter changes characterized by blood-brain barrier disruption, glial activation, oxidative stress, and oligodendrocyte loss following chronic cerebral hypoperfusion. Detailed characterization of this model may help to decipher the substrates associated with impaired memory and move toward a more integrated therapy of vascular cognitive impairment.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenxian Li ◽  
Di Wei ◽  
Zheng Zhu ◽  
Xiaomei Xie ◽  
Shuqin Zhan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Signaling Pathways ◽  
Neuronal Death ◽  
Neuronal Apoptosis ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Stat3 Pathway ◽  
Stat3 Signaling

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.

scholarly journals Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

2020 ◽  
Vol 21 (6) ◽  
pp. 2176 ◽  
Author(s):  
Amelia Nur Vidyanti ◽  
Jia-Yu Hsieh ◽  
Kun-Ju Lin ◽  
Yao-Ching Fang ◽  
Ismail Setyopranoto ◽  
...  
Keyword(s):  
Animal Model ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Chronic Phase ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Hippocampal Atrophy ◽  
Tnf Α

The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30–50% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-α, IL-1β, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR/Cas9 knockout plasmid restored TNF-α, IL-1β, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI.

scholarly journals Deficiency of Nrf2 exacerbates white matter damage and microglia/macrophage levels in a mouse model of vascular cognitive impairment

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Emma Sigfridsson ◽  
Martina Marangoni ◽  
Giles E. Hardingham ◽  
Karen Horsburgh ◽  
Jill H. Fowler
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Brain Barrier ◽  
Cerebral Hypoperfusion ◽  
Blood Brain ◽  
Barrier Breakdown ◽  
White Matter Pathology ◽  
Blood Brain Barrier Breakdown

Abstract Background Chronic cerebral hypoperfusion causes damage to the brain’s white matter underpinning vascular cognitive impairment. Inflammation and oxidative stress have been proposed as key pathophysiological mechanisms of which the transcription factor Nrf2 is a master regulator. We hypothesised that white matter pathology, microgliosis, blood-brain barrier breakdown and behavioural deficits induced by chronic hypoperfusion would be exacerbated in mice deficient in the transcription factor Nrf2. Methods Mice deficient in Nrf2 (male heterozygote or homozygous for Nrf2 knockout) or wild-type littermates on a C57Bl6/J background underwent bilateral carotid artery stenosis (BCAS) to induce chronic cerebral hypoperfusion or sham surgery and survived for a further 6 weeks. White matter pathology was assessed with MAG immunohistochemistry as a marker of altered axon-glial integrity; alterations to astrocytes and microglia/macrophages were assessed with GFAP and Iba1 immunohistochemistry, and blood-brain barrier breakdown was assessed with IgG immunohistochemistry. Behavioural alterations were assessed using 8-arm radial arm maze, and alterations to Nrf2-related and inflammatory-related genes were assessed with qRT-PCR. Results Chronic cerebral hypoperfusion induced white matter pathology, elevated microglial/macrophage levels and blood-brain barrier breakdown in white matter tracts that were increased in Nrf2+/− mice and further exacerbated by the complete absence of Nrf2. Chronic hypoperfusion induced white matter astrogliosis and induced an impairment in behaviour assessed with radial arm maze; however, these measures were not affected by Nrf2 deficiency. Although Nrf2-related antioxidant gene expression was not altered by chronic cerebral hypoperfusion, there was evidence for elevated pro-inflammatory related gene expression following chronic hypoperfusion that was not affected by Nrf2 deficiency. Conclusions The results demonstrate that the absence of Nrf2 exacerbates white matter pathology and microgliosis following cerebral hypoperfusion but does not affect behavioural impairment.

scholarly journals Chronic Cerebral Hypoperfusion Induces Vascular Plasticity and Hemodynamics but Also Neuronal Degeneration and Cognitive Impairment

2015 ◽  
Vol 35 (8) ◽  
pp. 1249-1259 ◽  
Author(s):  
Zhen Jing ◽  
Changzheng Shi ◽  
Lihui Zhu ◽  
Yonghui Xiang ◽  
Peihao Chen ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Carotid Artery ◽  
Common Carotid Artery ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Common Carotid Artery Occlusion

Chronic cerebral hypoperfusion (CCH) induces cognitive impairment, but the compensative mechanism of cerebral blood flow (CBF) is not fully understood. The present study mainly investigated dynamic changes in CBF, angiogenesis, and cellular pathology in the cortex, the striatum, and the cerebellum, and also studied cognitive impairment of rats induced by bilateral common carotid artery occlusion (BCCAO). Magnetic resonance imaging (MRI) techniques, immunochemistry, and Morris water maze were employed to the study. The CBF of the cortex, striatum, and cerebellum dramatically decreased after right common carotid artery occlusion (RCCAO), and remained lower level at 2 weeks after BCCAO. It returned to the sham level from 3 to 6 weeks companied by the dilation of vertebral arteries after BCCAO. The number of microvessels declined at 2, 3, and 4 weeks but increased at 6 weeks after BCCAO. Neuronal degeneration occurred in the cortex and striatum from 2 to 6 weeks, but the number of glial cells dramatically increased at 4 weeks after BCCAO. Cognitive impairment of ischemic rats was directly related to ischemic duration. Our results suggest that CCH induces a compensative mechanism attempting to maintain optimal CBF to the brain. However, this limited compensation cannot prevent neuronal loss and cognitive impairment after permanent ischemia.

scholarly journals Comprehensive Evaluation of White Matter Damage and Neuron Death and Whole-Transcriptome Analysis of Rats With Chronic Cerebral Hypoperfusion

2019 ◽  
Vol 13 ◽  
Author(s):  
Wenxian Li ◽  
Di Wei ◽  
Jianye Liang ◽  
Xiaomei Xie ◽  
Kangping Song ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Neuronal Death ◽  
Chronic Cerebral Hypoperfusion ◽  
Differentially Expressed ◽  
Cerebral Hypoperfusion ◽  
Neuron Death ◽  
White Matter Damage ◽  
Morris Water Maze Task ◽  
Whole Transcriptome

Background/AimsChronic cerebral hypoperfusion (CCH) is induced by chronic deficit of brain perfusion, contributes to a persistent or progressive cognitive dysfunction, which is characterized by diverse neuropathological manifestations. There are currently no effective medications available. White matter damage (WMD) and cortical neuron death may be caused by CCH, which are related to cognitive impairment, while the underlying molecular mechanisms remain unclear. In the study, a database of the transcriptome level was built to determine potential biomarkers in cortex of CCH.MethodsCCH was induced in male Sprague-Dawley rats by permanent occlusion of the bilateral common carotid arteries. Rats were randomly divided into three groups: Sham-operated group (n = 24), the 4th and 8th week of CCH groups (total = 56, n = 28 for each group). Cognitive function was evaluated using the Morris water maze task. WMD and neuron damage were detected using diffusion tensor imaging and histological analysis, respectively. Western blotting analysis of various markers was used to examine neuronal death. Whole-transcriptome microarray was performed to assess mRNA, circRNA, and lncRNA expression profiles at 4th and 8th weeks after CCH. Diversified bioinformatic tools were performed to analyze and predict the key biological processes and signaling pathways of differentially expressed RNAs and co-expressed potential target genes. Co-expression networks of mRNA–circRNA–miRNA and lncRNA–mRNA were constructed.ResultsCompared to the sham group, cognitive impairment, disintegration of white matter, blood-brain barrier damage and neuron death were induced by CCH. Neuron death including apoptosis and necroptosis might occur in the cortex of CCH. We constructed the regulatory networks of whole-transcriptomic including differentially expressed mRNAs, circRNAs, and lncRNAs, and related biological functions and pathways involved in neurological disease, cell death and survival, energy and metabolism, et al. Our results also indicated that Cyr61 mRNA may play a role in the CCH-related cortical neuronal death.ConclusionWMD and cortical neuronal death are worthy of attention in the pathogenesis of CCH. Additionally, the present results provide potential evidence at the whole-transcription level for CCH, offering candidate biomarkers and therapeutic targets.

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