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

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.

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 The role of inflammasomes in vascular cognitive impairment

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.

Vascular cognitive impairment and Alzheimer’s disease: role of cerebral hypoperfusion and oxidative stress

2012 ◽  
Vol 385 (10) ◽  
pp. 953-959 ◽  
Author(s):  
Hyun Ah Kim ◽  
Alyson A. Miller ◽  
Grant R. Drummond ◽  
Amanda G. Thrift ◽  
Thiruma V. Arumugam ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Vascular Cognitive Impairment ◽  
Cerebral Hypoperfusion ◽  
And Oxidative Stress

Abstract P772: Complement C3a Receptor Deletion is Neuroprotective in a Murine Model of Vascular Cognitive Impairment

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Saif Ahmad ◽  
Muhammed Nadeem ◽  
Adam Kindelin ◽  
Laura Mahady ◽  
Kanchan Bhatia ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Behavioral Outcomes ◽  
Vascular Cognitive Impairment ◽  
Laser Speckle ◽  
Cerebral Hypoperfusion ◽  
Protein Biochemistry ◽  
Bilateral Common Carotid Artery ◽  
Contrast Analysis ◽  
Poor Outcomes

Background: Chronic cerebral hypoperfusion (CCH) leads to vascular contributions to cognitive impairment and dementia (VCID). We and others have reported that either the genetic deficiency of complement C3a receptor (C3aR) or its pharmacological inhibition in rodents protect against cerebral ischemia. Hypothesis: CCH augments VCID via overactivation of C3aR in brain. Methods: Male C3aR knockout (C3aR -/- ) and wild-type (C3aR +/+ ) mice (Age:12 weeks; N=8-10/gp) were subjected to either VCID with bilateral common carotid artery stenosis (BCAS) or sham surgery. At 4-mo post-BCAS, changes in cerebral blood flow (CBF), hippocampal atrophy (HA), white matter degeneration (WMD) and ventricular size were determined with laser speckle contrast analysis and magnetic resonance imaging. Behavioral outcomes were evaluated using Morris water maze (MWM) and novel object recognition (NOR). Histopathology with Luxol-Fast Blue (LFB) staining, and protein biochemistry with Western blotting were also performed. Results: BCAS resulted in reduced CBF, inducing HA, WMD and ventricle enlargement in both groups compared to their sham controls. These deleterious findings were attenuated in C3aR -/- compared to C3aR +/+ mice. Moreover, the C3aR -/- -BCAS group performed significantly better than C3aR +/+ -BCAS group in MWM and NOR tests; however, mice subjected to BCAS never outperformed their sham-groups. WMD demonstrated by LFB-staining and reduced expression of myelin basic protein and tight junction proteins (ZO-1 and Occludin) in mice subjected to BCAS was mitigated in C3aR -/- as compared to C3aR +/+ mice. C3aR +/+ -BCAS also showed significantly higher expression of C3a in plasma and C3aR in brain lysates compared to their sham-controls. Conclusion: CCH augments C3aR activation leading to poor outcomes in VCID. Therefore, future studies in cell-specific mutant mice are warranted to understand the pathological role of C3aR in VCID.

High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics

2019 ◽  
Vol 20 (14) ◽  
pp. 1474-1485 ◽  
Author(s):  
Eyaldeva C. Vijayakumar ◽  
Lokesh Kumar Bhatt ◽  
Kedar S. Prabhavalkar
Keyword(s):  
Myocardial Infarction ◽  
Vagus Nerve Stimulation ◽  
Nuclear Protein ◽  
Therapeutic Potential ◽  
High Mobility ◽  
Dna Binding Protein ◽  
High Mobility Group ◽  
Eukaryotic Cells ◽  
Hmgb1 Protein

High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.

scholarly journals The Role of High Triglycerides Level in Predicting Cognitive Impairment: A Review of Current Evidence

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 2118
Author(s):  
Alina Mihaela Dimache ◽  
Delia Lidia Șalaru ◽  
Radu Sascău ◽  
Cristian Stătescu
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Lifestyle Modification ◽  
Cognitive Disorders ◽  
Current Evidence ◽  
Barrier Dysfunction ◽  
Serum Triglycerides ◽  
Cerebral Amyloidosis ◽  
The Relationship

The burden of cognitive disorders is huge and still growing, however the etiology and the degree of cognitive impairment vary considerably. Neurodegenerative and vascular mechanisms were most frequently assessed in patients with dementia. Recent studies have shown the possible involvement of triglycerides levels in cognitive function through putative mechanisms such as brain blood barrier dysfunction or amyloid metabolism imbalance, but not all research in the field found this association. Several clinical studies evaluated the relationship between different forms of cognitive decline and levels of serum triglycerides, independent of other cardiovascular risk factors. This review focuses on the role of triglycerides in cognitive decline, cerebral amyloidosis and vascular impairment. Considering that the management of hypertriglyceridemia benefits from lifestyle modification, diet, and specific drug therapy, future studies are requested to appraise the triglycerides–cognitive impairment relationship.

scholarly journals Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hongseok Yoo ◽  
Yunjoo Im ◽  
Ryoung-Eun Ko ◽  
Jin Young Lee ◽  
Junseon Park ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Validation Cohort ◽  
High Mobility ◽  
Kinase Domain ◽  
High Mobility Group ◽  
Rank Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Derivation Cohort ◽  
The Difference

AbstractThe role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.

scholarly journals LPS Primes Brain Responsiveness to High Mobility Group Box-1 Protein

2021 ◽  
Vol 14 (6) ◽  
pp. 558
Author(s):  
Verena Peek ◽  
Lois M. Harden ◽  
Jelena Damm ◽  
Ferial Aslani ◽  
Stephan Leisengang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Area Postrema ◽  
High Mobility ◽  
High Mobility Group ◽  
Direct Access ◽  
Significant Release ◽  
Factor Α ◽  
Culture Supernatants

High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood–brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms.

scholarly journals Mild Cognitive Impairment in Clinical Practice: A Review Article

2018 ◽  
Vol 33 (8) ◽  
pp. 500-507 ◽  
Author(s):  
Sukanya Jongsiriyanyong ◽  
Panita Limpawattana
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Preventive Intervention ◽  
Lifestyle Modification ◽  
The Elderly ◽  
Vascular Cognitive Impairment ◽  
Review Article ◽  
Subjective Cognitive Impairment ◽  
Rate Of Progression

The spectrum of cognitive decline in the elderly ranges from what can be classified as normal cognitive decline with aging to subjective cognitive impairment to mild cognitive impairment (MCI) to dementia. This article reviewed the up-to-date evidence of MCI including the diagnostic criteria of MCI due to Alzheimer’s disease, vascular cognitive impairment and MCI due to Parkinson disease, management and preventive intervention of MCI. There are various etiologies of MCI, and a large number of studies have been conducted to ascertain the practical modalities of preserving cognition in predementia stages. Lifestyle modification, such as aerobic exercise, is an approved modality to preserve cognitive ability and decrease the rate of progression to dementia, as well as being recommended for frailty prevention.

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