Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease

Sasaki, Tatsuya; Liu, Keyue; Agari, Takashi; Yasuhara, Takao; Morimoto, Jun; Okazaki, Mihoko; Takeuchi, Hayato; Toyoshima, Atsushi; Sasada, Susumu; Shinko, Aiko; Kondo, Akihiko; Kameda, Masahiro; Miyazaki, Ikuko; Asanuma, Masato; Borlongan, Cesario V.; Nishibori, Masahiro; Date, Isao

doi:10.1016/j.expneurol.2015.11.003

Cited by 120 publications

(113 citation statements)

References 45 publications

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“…Protection against BBB disruption in ischemic and neurodegenerative models using monoclonal anti-HMGB1 antibodies neutralising all redox isoforms has previously been reported [17, 28]. In addition, Zhang et al [22] have demonstrated that HMGB1 with no specified redox state acts directly on vascular endothelial cells and pericytes to induce morphological changes, thus increasing BBB permeability.…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

et al. 2018

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Background: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. Methods: Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. Results and Conclusions: Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury.

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Section: Discussionmentioning

confidence: 99%

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

et al. 2018

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“…Both endogenous as well as exogenous means exist to combat this imbalance including the proteolytic release of sRAGE and sTM, both of which selectively bind up HMGB1 (possibly other alarmins) preventing engagement of RAGE or TLRs. This also allows for the development of novel therapeutic targets that act like sRAGE and sTM, in a manner less burdensome and potentially with fewer side effects than by administering neutralizing antibodies to HMGB1, such as recently used by others in rat models of stroke, TBI, and Parkinson’s disease [49, 50, 69]. …”

Section: Discussionmentioning

confidence: 99%

HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease

Festoff

Sajja

Dreden

et al. 2016

J Neuroinflammation

173

123

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Background: The blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer's disease (AD) that precedes the hallmarks of amyloid beta (amyloid β) plaque deposition and neuronal neurofibrillary tangle (NFT) formation. A damaged BBB correlates directly with neuroinflammation involving microglial activation and reactive astrogliosis, which is associated with increased expression and/or release of high-mobility group box protein 1 (HMGB1) and thrombin. However, the link between the presence of these molecules, BBB damage, and progression to neurodegeneration in AD is still elusive. Therefore, we aimed to profile and validate non-invasive clinical biomarkers of BBB dysfunction and neuroinflammation to assess the progression to neurodegeneration in mild cognitive impairment (MCI) and AD patients. Methods: We determined the serum levels of various proinflammatory damage-associated molecules in aged control subjects and patients with MCI or AD using validated ELISA kits. We then assessed the specific and direct effects of such molecules on BBB integrity in vitro using human primary brain microvascular endothelial cells or a cell line. Results: We observed a significant increase in serum HMGB1 and soluble receptor for advanced glycation end products (sRAGE) that correlated well with amyloid beta levels in AD patients (vs. control subjects). Interestingly, serum HMGB1 levels were significantly elevated in MCI patients compared to controls or AD patients. In addition, as a marker of BBB damage, soluble thrombomodulin (sTM) antigen, and activity were significantly (and distinctly) increased in MCI and AD patients. Direct in vitro BBB integrity assessment further revealed a significant and concentration-dependent increase in paracellular permeability to dextrans by HMGB1 or α-thrombin, possibly through disruption of zona occludins-1 bands. Pre-treatment with anti-HMGB1 monoclonal antibody blocked HMGB1 effects and leaving BBB integrity intact. Conclusions: Our current studies indicate that thrombin and HMGB1 are causal proximate proinflammatory mediators of BBB dysfunction, while sTM levels may indicate BBB endothelial damage; HMGB1 and sRAGE might serve as clinical biomarkers for progression and/or therapeutic efficacy along the AD spectrum.

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“…Our results show that (Figs 5A, 5B, 6A & 6B) feeding blueberries prevents the enhanced levels of PICs IL1, IL4 and IL 18 in addition to TLR4 and HMGB1, thereby preventing the catabolism of biogenic amines [55, 56]. HMGB1 is an essential cytokine that mediates the response to infection, injury and inflammation [57, 58]. The occurrence of HMGB1 in the nucleus is governed by posttranslational modifications of the cellular reactions.…”

Section: Discussionmentioning

confidence: 99%

The Anti-Inflammatory Effects of Blueberries in an Animal Model of Post-Traumatic Stress Disorder (PTSD)

Ebenezer

Wilson

et al. 2016

PLoS ONE

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Post-traumatic stress disorder (PTSD) is a trauma and stressor-related disorder that results in a prolonged stress response. It is associated with increased oxidative stress and inflammation in the prefrontal cortex (PFC) and hippocampus (HC). The only approved therapy for PTSD is selective serotonin re-uptake inhibitors (SSRIs), but their efficacy is marginal. Recently, we demonstrated that over-production of norepinephrine (NE) as the possible reason for the lack of efficacy of SSRIs. Hence, there is a need for novel therapeutic approaches for the treatment of PTSD. In this study, we investigated the anti-inflammatory role of blueberries in modulating inflammatory markers and neurotransmitter levels in PTSD. Rats were fed either a blueberry enriched (2%) or a control diet. Rats were exposed to cats for one hour on days 1 and 11 of a 31-day schedule to simulate traumatic conditions. The rats were also subjected to psychosocial stress via daily cage cohort changes. At the end of the study, the rats were euthanized and the PFC and HC were isolated. Monoamines were measured by high-performance liquid chromatography. Reactive oxygen species (ROS), gene and protein expression levels of inflammatory cytokines were also measured. In our PTSD model, NE levels were increased and 5-HT levels were decreased when compared to control. In contrast, a blueberry enriched diet increased 5-HT without affecting NE levels. The rate limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase were also studied and they confirmed our findings. The enhanced levels free radicals, gene and protein expression of inflammatory cytokines seen in the PTSD group were normalized with a blueberry enriched diet. Decreased anxiety in this group was shown by improved performance on the elevated plus-maze. These findings indicate blueberries can attenuate oxidative stress and inflammation and restore neurotransmitter imbalances in a rat model of PTSD.

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Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease

Cited by 120 publications

References 45 publications

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer’s disease

The Anti-Inflammatory Effects of Blueberries in an Animal Model of Post-Traumatic Stress Disorder (PTSD)

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