Therapeutic time window of anti-high mobility group box-1 antibody administration in mouse model of spinal cord injury

Nakajo, Masahide; Uezono, Naohiro; Nakashima, Hideyuki; Wake, Hidenori; Komiya, Setsuro; Nishibori, Masahiro; Nakashima, Kinichi

doi:10.1016/j.neures.2018.03.004

Cited by 15 publications

(26 citation statements)

References 35 publications

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“…The analysis of receptors involved in the action of HMGB1 using receptor-knockout mice implied that RAGE and TLR-4 may play roles in the action of HMGB1 [17]. Anti-HMGB1 mAb therapy was applicable to spinal cord injury in a contusion animal model [97,98]. Prior treatment with anti-HMGB1 mAb in mice transplanted with human iPS-derived neuronal stem cells yielded a dramatic improvement in locomotion recovery after spinal cord injury [98].…”

Section: Traumatic Brain Injury and Bbb Disruptionmentioning

confidence: 99%

“…The combination therapy produced synergistic effects on the contusion-induced spinal cord injury in mice. The beneficial effects of anti-HMGB1 mAb probably come from the inhibition of the initial formation of edema at the injured site and subsequent suppression of glial cell activation [97,98] because there was a therapeutic time window of 6 h for anti-HMGB1 treatment in this animal model [97], which was comparable to that of hemorrhage brain injury in rats [16]. These results strongly suggest that HMGB1 exerts BBB-disrupting effects at the very acute phase of brain injuries [25,26] (Figure 4).…”

Section: Traumatic Brain Injury and Bbb Disruptionmentioning

confidence: 99%

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High Mobility Group Box-1 and Blood–Brain Barrier Disruption

Nishibori

Wang

Ousaka

et al. 2020

Cells

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Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood–brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer’s amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption.

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Section: Traumatic Brain Injury and Bbb Disruptionmentioning

confidence: 99%

Section: Traumatic Brain Injury and Bbb Disruptionmentioning

confidence: 99%

High Mobility Group Box-1 and Blood–Brain Barrier Disruption

Nishibori

Wang

Ousaka

et al. 2020

Cells

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“…One research showed that acute intraperitoneal use of HMGB1 neutralizing antibody failed to provide protection after SCI [31], which suggested that small molecule inhibitors of HMGB1 such as glycyrrhizin may be preferable to blocking antibodies since these molecules can bypass the blood-spinal cord barrier more effectively. On the other hand, beneficial effects of anti-HMGB1 mAb for SCI depended on a proper time window for drug administration as demonstrated previously [59]. In addition, it was reported that prior treatment with anti-HMGB-1 antibody enhanced human neural stem cell transplantation-mediated functional recovery after SCI, and this effect was mediated by increased synaptic connectivity between increased preserved host neurons and transplant-derived neurons [60], which was similar as increased neuronal survival by FPS-ZM1 in this study.…”

Section: Discussionmentioning

confidence: 53%

“…In this study, the inhibition of release of HMGB1 was not found by glycyrrhizin treatment after SCI (data not shown), and we proposed that glycyrrhizin could inhibit the receptor activation of HMGB1 as shown by the decreased percentage of RAGE-positive cells in F4/80-positive cells after SCI. Besides the small molecules, anti-HMGB1 monoclonal antibody (mAb) had been demonstrated to neutralize the released HMGB1, prevent the inflammation cascade, and afford a therapeutic effect in ischemic brain injury, traumatic brain injury, Parkinson’s disease, and SCI [ 14 , 56 – 59 ]. One research showed that acute intraperitoneal use of HMGB1 neutralizing antibody failed to provide protection after SCI [ 31 ], which suggested that small molecule inhibitors of HMGB1 such as glycyrrhizin may be preferable to blocking antibodies since these molecules can bypass the blood-spinal cord barrier more effectively.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting HMGB1-RAGE axis prevents pro-inflammatory macrophages/microglia polarization and affords neuroprotection after spinal cord injury

Fan

Tang

Chen

et al. 2020

J Neuroinflammation

130

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Background Spinal cord injury (SCI) favors a persistent pro-inflammatory macrophages/microglia-mediated response with only a transient appearance of anti-inflammatory phenotype of immune cells. However, the mechanisms controlling this special sterile inflammation after SCI are still not fully elucidated. It is known that damage-associated molecular patterns (DAMPs) released from necrotic cells after injury can trigger severe inflammation. High mobility group box 1(HMGB1), a ubiquitously expressed DNA binding protein, is an identified DAMP, and our previous study demonstrated that reactive astrocytes could undergo necroptosis and release HMGB1 after SCI in mice. The present study aimed to explore the effects and the possible mechanism of HMGB1on macrophages/microglia polarization, as well as the neuroprotective effects by HMGB1 inhibition after SCI. Methods In this study, the expression and the concentration of HMGB1 was determined by qRT-PCR, ELISA, and immunohistochemistry. Glycyrrhizin was applied to inhibit HMGB1, while FPS-ZM1 to suppress receptor for advanced glycation end products (RAGE). The polarization of macrophages/microglia in vitro and in vivo was detected by qRT-PCR, immunostaining, and western blot. The lesion area was detected by GFAP staining, while neuronal survival was examined by Nissl staining. Luxol fast blue (LFB) staining, DAB staining, and western blot were adopted to evaluate the myelin loss. Basso-Beattie-Bresnahan (BBB) scoring and rump-height Index (RHI) assay was applied to evaluate locomotor functional recovery. Results Our data showed that HMGB1 can be elevated and released from necroptotic astrocytes and HMGB1 could induce pro-inflammatory microglia through the RAGE-nuclear factor-kappa B (NF-κB) pathway. We further demonstrated that inhibiting HMGB1 or RAGE effectively decreased the numbers of detrimental pro-inflammatory macrophages/microglia while increased anti-inflammatory cells after SCI. Furthermore, our data showed that inhibiting HMGB1 or RAGE significantly decreased neuronal loss and demyelination, and improved functional recovery after SCI. Conclusions The data implicated that HMGB1-RAGE axis contributed to the dominant pro-inflammatory macrophages/microglia-mediated pro-inflammatory response, and inhibiting this pathway afforded neuroprotection for SCI. Thus, therapies designed to modulate immune microenvironment based on this cascade might be a prospective treatment for SCI.

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“…High Mobility Group Box-1 (HMGB1) is one of the damageassociated molecular patterns and has been reported to play an important role in the secondary injury following central nervous system (CNS) injuries: once released from damaged cells, it can bind to cell surface receptors, such as the receptor for advanced glycation end products, toll-like receptor (TLR) 2 and TLR4, which induce blood brain barrier (BBB) disruption and inflammatory response (Hayakawa et al, 2010;Lotze and Tracey, 2005;Zhang et al, 2011). We have previously shown that administration of anti-HMGB1 monoclonal antibody (mAb) after SCI in the early acute phase attenuate secondary damage and promoted motor functional recovery in mouse model (Nakajo et al, 2019;Uezono et al, 2018). Compared with untreated mice, those received anti-HMGB1 mAb showed an increase in neurite sprouting from spared axons, reduced-spinal cord swelling and -neuronal apoptosis, indicating decreased bloodspinal cord barrier (BSCB) disruption.…”

Section: Introductionmentioning

confidence: 99%