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

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.

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The role of high-mobility group box protein 1 in chronic cerebral hypoperfusion-induced vascular cognitive impairment animals

10.21203/rs.2.17046/v1 ◽

2019 ◽

Author(s):

Amelia Nur Vidyanti ◽

Jia-Yu Hsieh ◽

Kun-Ju Lin ◽

Yao-Ching Fang ◽

Ismail Setyopranoto ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

High Mobility ◽

Vascular Cognitive Impairment ◽

High Mobility Group ◽

Cerebral Hypoperfusion ◽

Hippocampal Atrophy ◽

Amyloid Pet ◽

Knock Out

Abstract Background: The molecular mechanisms of vascular cognitive impairment (VCI) are diverse and still in puzzle. VCI could be attributed to chronic cerebral hypoperfusion (CCH). CCH may cause a cascade of reactions involved in ischemia and neuro-inflammation which plays important roles in the pathophysiology of VCI. High-mobility group box protein 1 (HMGB1) is a non-histone protein that serves as a damage-associated molecular signal leading to cascades of inflammation. Increased level of HMGB1 has been established in the acute phase of CCH. However, the role of HMGB1 at the chronic phase of CCH remains elucidated. Methods: We performed modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice to induce CCH. We examined the cerebral blood flow (CBF) reduction by laser doppler flowmetry, the protein expression of HMGB1 and its pro-inflammatory cytokines (TNF-a, IL-1b, and IL-6) by western blotting and immunohistochemistry. The brain pathology was assessed by 7T-animal MRI and amyloid-b accumulation was assessed by amyloid-PET scanning. We further evaluated the effect of HMGB1 suppression by injecting CRISPR/Cas9 knock-out plasmid intra-hippocampus bilaterally. Results: There were reduction of CBF up to 50% which persisted three months after CCH. The modified-BCCAO animals developed significant cognitive decline. The 7T-MRI image showed hippocampal atrophy, although the amyloid-PET showed no significant amyloid-beta accumulation. Increased protein levels of HMGB1, TNF-a and IL-1b were found three months after BCCAO. HMGB1 suppression by CRISPR/Cas9 knock-out plasmid restored the CBF, IL-1B, TNF-alpha, IL-6, and attenuated hippocampal atrophy and cognitive decline. Conclusion: HMGB1 plays a pivotal role in the pathophysiology of the animal model of CCH and it might be a candidate as therapeutic targets of VCI.

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Increased level of HMGB1 induced by chronic cerebral hypoperfusion without evident of amyloid-beta accumulation in an animal model of vascular cognitive impairment

IBRO Reports ◽

10.1016/j.ibror.2019.07.226 ◽

2019 ◽

Vol 6 ◽

pp. S69

Author(s):

Amelia Nur Vidyanti ◽

Chaur-Jong Hu

Keyword(s):

Animal Model ◽

Cognitive Impairment ◽

Amyloid Beta ◽

Vascular Cognitive Impairment ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion

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A Mouse Model of Chronic Cerebral Hypoperfusion Characterizing Features of Vascular Cognitive Impairment

Methods in Molecular Biology - Cerebral Angiogenesis ◽

10.1007/978-1-4939-0320-7_8 ◽

2014 ◽

pp. 95-102 ◽

Cited By ~ 13

Author(s):

Masafumi Ihara ◽

Akihiko Taguchi ◽

Takakuni Maki ◽

Kazuo Washida ◽

Hidekazu Tomimoto

Keyword(s):

Cognitive Impairment ◽

Mouse Model ◽

Vascular Cognitive Impairment ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion

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

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.587403 ◽

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.

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Protective Role of S-Nitrosoglutathione (GSNO) Against Cognitive Impairment in Rat Model of Chronic Cerebral Hypoperfusion

Journal of Alzheimer s Disease ◽

10.3233/jad-121786 ◽

2013 ◽

Vol 34 (3) ◽

pp. 621-635 ◽

Cited By ~ 31

Author(s):

Je-Seong Won ◽

Jinsu Kim ◽

Balasubramaniam Annamalai ◽

Anandakumar Shunmugavel ◽

Inderjit Singh ◽

...

Keyword(s):

Cognitive Impairment ◽

Rat Model ◽

Protective Role ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion

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The Role of Autophagy in the Correlation Between Neuron Damage and Cognitive Impairment in Rat Chronic Cerebral Hypoperfusion

Molecular Neurobiology ◽

10.1007/s12035-016-0351-z ◽

2017 ◽

Vol 55 (1) ◽

pp. 776-791 ◽

Cited By ~ 17

Author(s):

Wenying Zou ◽

Yufei Song ◽

Yumei Li ◽

Yu Du ◽

Xiaojie Zhang ◽

...

Keyword(s):

Cognitive Impairment ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Neuron Damage

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The role of inflammasomes in vascular cognitive impairment

Molecular Neurodegeneration ◽

10.1186/s13024-021-00506-8 ◽

2022 ◽

Vol 17 (1) ◽

Author(s):

Luting Poh ◽

Wei Liang Sim ◽

Dong-Gyu Jo ◽

Quynh Nhu Dinh ◽

Grant R. Drummond ◽

...

Keyword(s):

Cognitive Impairment ◽

Critical Role ◽

Disease Onset ◽

The Elderly ◽

Vascular Cognitive Impairment ◽

Cerebral Hypoperfusion ◽

Early Event ◽

Cellular Mechanisms ◽

Structural Brain Damage

AbstractThere is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1β production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.

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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

Clinical Science ◽

10.1042/cs20160727 ◽

2017 ◽

Vol 131 (19) ◽

pp. 2451-2468 ◽

Cited By ~ 77

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.

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