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

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

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 μg/4 μl) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1. day and astrocytes at 7. days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1β and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-OHDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BBB associated with the disease.

Original languageEnglish
Pages (from-to)220-231
Number of pages12
JournalExperimental Neurology
Volume275
DOIs
Publication statusPublished - Jan 1 2016

Fingerprint

Parkinson Disease
Monoclonal Antibodies
Antibodies
Oxidopamine
Astrocytes
Dopaminergic Neurons
Blood-Brain Barrier
Neurons
Cytokines
Inflammation
Neuroprotection
Behavioral Symptoms
Injections
Extracellular Space
Microglia
Neuroprotective Agents
Nuclear Proteins
Interleukin-1
Intravenous Administration
Sprague Dawley Rats

Keywords

  • Antibody therapy
  • Blood-brain-barrier
  • High mobility group box 1
  • Inflammation
  • Neuroprotection
  • Parkinson's disease

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

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, Atsuhiko; Sasada, Susumu; Shinko, Aiko; Kondo, Akihiko; Kameda, Masahiro; Miyazaki, Ikuko; Asanuma, Masato; Borlongan, Cesario V.; Nishibori, Masahiro; Date, Isao.

In: Experimental Neurology, Vol. 275, 01.01.2016, p. 220-231.

Research output: Contribution to journalArticle

Sasaki, Tatsuya ; Liu, Keyue ; Agari, Takashi ; Yasuhara, Takao ; Morimoto, Jun ; Okazaki, Mihoko ; Takeuchi, Hayato ; Toyoshima, Atsuhiko ; Sasada, Susumu ; Shinko, Aiko ; Kondo, Akihiko ; Kameda, Masahiro ; Miyazaki, Ikuko ; Asanuma, Masato ; Borlongan, Cesario V. ; Nishibori, Masahiro ; Date, Isao. / Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease. In: Experimental Neurology. 2016 ; Vol. 275. pp. 220-231.
@article{ab3cafdf3c8c4c428e858f184d74262f,
title = "Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease",
abstract = "The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 μg/4 μl) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1. day and astrocytes at 7. days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1β and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-OHDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BBB associated with the disease.",
keywords = "Antibody therapy, Blood-brain-barrier, High mobility group box 1, Inflammation, Neuroprotection, Parkinson's disease",
author = "Tatsuya Sasaki and Keyue Liu and Takashi Agari and Takao Yasuhara and Jun Morimoto and Mihoko Okazaki and Hayato Takeuchi and Atsuhiko Toyoshima and Susumu Sasada and Aiko Shinko and Akihiko Kondo and Masahiro Kameda and Ikuko Miyazaki and Masato Asanuma and Borlongan, {Cesario V.} and Masahiro Nishibori and Isao Date",
year = "2016",
month = "1",
day = "1",
doi = "10.1016/j.expneurol.2015.11.003",
language = "English",
volume = "275",
pages = "220--231",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Anti-high mobility group box 1 antibody exerts neuroprotection in a rat model of Parkinson's disease

AU - Sasaki, Tatsuya

AU - Liu, Keyue

AU - Agari, Takashi

AU - Yasuhara, Takao

AU - Morimoto, Jun

AU - Okazaki, Mihoko

AU - Takeuchi, Hayato

AU - Toyoshima, Atsuhiko

AU - Sasada, Susumu

AU - Shinko, Aiko

AU - Kondo, Akihiko

AU - Kameda, Masahiro

AU - Miyazaki, Ikuko

AU - Asanuma, Masato

AU - Borlongan, Cesario V.

AU - Nishibori, Masahiro

AU - Date, Isao

PY - 2016/1/1

Y1 - 2016/1/1

N2 - The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 μg/4 μl) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1. day and astrocytes at 7. days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1β and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-OHDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BBB associated with the disease.

AB - The high mobility group box-1 (HMGB1) exists as an architectural nuclear protein in the normal state, but displays an inflammatory cytokine-like activity in the extracellular space under pathological condition. Inflammation in the pathogenesis of Parkinson's disease (PD) has been documented. In this study, we investigated the involvement of HMGB1 in the pathology and the neuroprotective effects of neutralizing anti-HMGB1 monoclonal antibody (mAb) on an animal model of PD. Adult female Sprague-Dawley rats were initially injected with 6-hydroxydopmaine (6-OHDA, 20 μg/4 μl) into the right striatum, then anti-HMGB1 mAb (1 mg/kg), or control mAb was intravenously administered immediately, at 6 and 24 h after 6-OHDA injection. The treatment with anti-HMGB1 mAb significantly preserved dopaminergic neurons in substantia nigra pars compacta and dopaminergic terminals inherent in the striatum, and attenuated PD behavioral symptoms compared to the control mAb-treated group. HMGB1 was retained in the nucleus of neurons and astrocytes by inhibiting the proinflammation-induced oxidative stress in the anti-HMGB1 mAb-treated group, whereas HMGB1 translocation was observed in neurons at 1. day and astrocytes at 7. days after 6-OHDA injection in the control mAb-treated group. Anti-HMGB1 mAb inhibited the activation of microglia, disruption of blood-brain-barrier (BBB), and the expression of inflammation cytokines such as IL-1β and IL-6. These results suggested that HMGB1 released from neurons and astrocytes was at least partly involved in the mechanism and pathway of degeneration of dopaminergic neurons induced by 6-OHDA exposure. Intravenous administration of anti-HMGB1 mAb stands as a novel therapy for PD possibly acting through the suppression of neuroinflammation and the attenuation of disruption of BBB associated with the disease.

KW - Antibody therapy

KW - Blood-brain-barrier

KW - High mobility group box 1

KW - Inflammation

KW - Neuroprotection

KW - Parkinson's disease

UR - http://www.scopus.com/inward/record.url?scp=84947798703&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84947798703&partnerID=8YFLogxK

U2 - 10.1016/j.expneurol.2015.11.003

DO - 10.1016/j.expneurol.2015.11.003

M3 - Article

VL - 275

SP - 220

EP - 231

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

ER -