Anti–High Mobility Group Box 1 Antibody Therapy May Prevent Cognitive Dysfunction After Traumatic Brain Injury

Okuma, Yu; Wake, Hidenori; Takamatsu, Kiyoshi; Takahashi, Yu; Hishikawa, Tomohito; Yasuhara, Takao; Mori, Shuji; Takahashi, Hideo; Date, Isao; Nishibori, Masahiro

doi:10.1016/j.wneu.2018.10.164

Cited by 30 publications

(30 citation statements)

References 34 publications

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“…The female brain may be pre-conditioned to proinflammatory factors that attenuate radiation responses compared to their male counterparts. This effect may involve the HMGB1 protein, an important proinflammatory cytokine capable of activating and perpetuating inflammation in the brain, in part through interactions with TLR4 receptors (Maroso et al, 2010;Vezzani et al, 2011;Yao et al, 2013;Fujita et al, 2016;Bianchi et al, 2017;Paudel et al, 2018;Okuma et al, 2019;Webster et al, 2019). The capability of radiation exposure to preferentially activate this classic inflammatory signaling pathway in male mice is provocative, and supported by our data showing that immunoreactivity of HMGB1 and TLR4 in the hippocampus was significantly increased in male mice 15 weeks following irradiation, a response that was not observed in female mice.…”

Section: Discussionsupporting

confidence: 70%

“…One such pathway includes high mobility group box protein 1 (HMGB1), a ubiquitous nuclear protein that can be released by microglia (and other immune cells) to bind and activate the transmembrane, pattern recognition receptors for advanced glycation end products (RAGE), and toll-like receptor 4 (TLR4) on neurons and glia (Bianchi et al, 2017;Paudel et al, 2018). HMGB1 and TLR4 have attracted recent attention due to their roles in mediating traumatic brain injury (Fujita et al, 2016;Webster et al, 2019), Alzheimer's pathology (Fujita et al, 2016), neuroinflammatory conditions (Trotta et al, 2014), epileptogenesis (Paudel et al, 2018), and cognitive impairments (Paudel et al, 2018), thereby providing logical targets for intervention (Fujita et al, 2016;Okuma et al, 2019). These prior findings also suggested the potential importance of these inflammatory pathways in regulating the response of the irradiated brain, although purported sex-specific differences remained largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Sex-Specific Cognitive Deficits Following Space Radiation Exposure

Parihar

Angulo

Allen

et al. 2020

Front. Behav. Neurosci.

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The radiation fields in space define tangible risks to the health of astronauts, and significant work in rodent models has clearly shown a variety of exposure paradigms to compromise central nervous system (CNS) functionality. Despite our current knowledge, sex differences regarding the risks of space radiation exposure on cognitive function remain poorly understood, which is potentially problematic given that 30% of astronauts are women. While work from us and others have demonstrated pronounced cognitive decrements in male mice exposed to charged particle irradiation, here we show that female mice exhibit significant resistance to adverse neurocognitive effects of space radiation. The present findings indicate that male mice exposed to low doses (≤30 cGy) of energetic (400 MeV/n) helium ions (4 He) show significantly higher levels of neuroinflammation and more extensive cognitive deficits than females. Twelve weeks following 4 He ion exposure, irradiated male mice demonstrated significant deficits in object and place recognition memory accompanied by activation of microglia, marked upregulation of hippocampal Toll-like receptor 4 (TLR4), and increased expression of the pro-inflammatory marker high mobility group box 1 protein (HMGB1). Additionally, we determined that exposure to 4 He ions caused a significant decline in the number of dendritic branch points and total dendritic length along with the hippocampus neurons in female mice. Interestingly, only male mice showed a significant decline of dendritic spine density following irradiation. These data indicate that fundamental differences in inflammatory cascades between male and female mice may drive divergent CNS radiation responses that differentially impact the structural plasticity of neurons and neurocognitive outcomes following cosmic radiation exposure.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Sex-Specific Cognitive Deficits Following Space Radiation Exposure

Parihar

Angulo

Allen

et al. 2020

Front. Behav. Neurosci.

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“…Its worth noting that, recently anti‐HMGB1 mAb prevented cognitive dysfunction induced by TBI implicating the role of HMGB1 in TBI induced cognitive decline (Okuma et al . ). In this regard, HMGB1 might be a suitable candidate to be modeled as a therapy that can retard the epileptic seizure, as well as ameliorate cognitive decline.…”

Section: Future Perspective Of Hmgb1mentioning

confidence: 97%

“…Hence, an immediate task would be to investigate the plausible role of the HMGB1 protein in epilepsy induced cognitive decline, which would further pave the way toward designing therapy that would improve the quality of life of PWE by ameliorating cognitive decline. Its worth noting that, recently anti-HMGB1 mAb prevented cognitive dysfunction induced by TBI implicating the role of HMGB1 in TBI induced cognitive decline (Okuma et al 2018). In this regard, HMGB1 might be a suitable candidate to be modeled as a therapy that can retard the epileptic seizure, as well as ameliorate cognitive decline.…”

Section: Future Perspective Of Hmgb1mentioning

confidence: 97%

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

Paudel

Semple

Jones

et al. 2019

Journal of Neurochemistry

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Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti‐epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high‐mobility group box protein 1 (HMGB1), a DNA‐binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1‐targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.

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“…The antibody, termed #10-22, recognizes an epitope in the repetitive Cterminal sequence. Successful therapeutic interventions are reported in a number of experimental neuro-inflammatory conditions, including stroke (70), traumatic brain injury (71), cognitive dysfunction after traumatic brain injury (72), spinal cord injury (73), epilepsy (74,75), blood brain barrier dysfunction after CNS ischemia (76), hemorrhageinduced brain injury (77), neuropathic pain (78)(79)(80)(81)(82)(83), and neuropathic pain-related depressive behavior (84). The antibody has also demonstrated beneficial effects in severe mouse influenza models (85,86).…”

Section: Anti-hmgb1 Mab #10-22mentioning

confidence: 99%

Targeting Inflammation Driven by HMGB1

2020

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High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and outside of cells. Extracellular HMGB1 has been extensively studied for its prototypical alarmin functions activating innate immunity, after being actively released from cells or passively released upon cell death. TLR4 and RAGE operate as the main HMGB1 receptors. Disulfide HMGB1 activates the TLR4 complex by binding to MD-2. The binding site is separate from that of LPS and it is now feasible to specifically interrupt HMGB1/TLR4 activation without compromising protective LPS/TLR4-dependent functions. Another important therapeutic strategy is established on the administration of HMGB1 antagonists precluding RAGE-mediated endocytosis of HMGB1 and HMGB1-bound molecules capable of activating intracellular cognate receptors. Here we summarize the role of HMGB1 in inflammation, with a focus on recent findings on its mission as a damageassociated molecular pattern molecule and as a therapeutic target in inflammatory diseases. Recently generated HMGB1-specific inhibitors for treatment of inflammatory conditions are discussed.

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Anti–High Mobility Group Box 1 Antibody Therapy May Prevent Cognitive Dysfunction After Traumatic Brain Injury

Cited by 30 publications

References 34 publications

Sex-Specific Cognitive Deficits Following Space Radiation Exposure

Sex-Specific Cognitive Deficits Following Space Radiation Exposure

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

Targeting Inflammation Driven by HMGB1

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