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Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats

View Article: PubMed Central - PubMed

ABSTRACT

As one of the most lethal stroke subtypes, intracerebral hemorrhage (ICH) is acknowledged as a serious clinical problem lacking effective treatment. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. High mobility group box-1 (HMGB1) is a ubiquitous and abundant nonhistone DNA-binding protein, and is also an important proinflammatory molecule once released into the extracellular space from the nuclei. Here, we show that treatment with neutralizing anti-HMGB1 mAb (1 mg/kg, i.v. twice) remarkably ameliorated ICH-injury induced by local injection of collagenase IV in the striatum of rats. Administration of anti-HMGB1 mAb inhibited the release of HMGB1 into the extracellular space in the peri-hematomal region, reduced serum HMGB1 levels and decreased brain edema by protecting blood-brain barrier integrity, in association with decreased activated microglia and the expression of inflammation-related factors at 24 h after ICH. Consequently, anti-HMGB1 mAb reduced the oxidative stress and improved the behavioral performance of rats. These results strongly indicate that HMGB1 plays a critical role in the development of ICH-induced secondary injury through the amplification of plural inflammatory responses. Intravenous injection of neutralizing anti-HMGB1 mAb has potential as a novel therapeutic strategy for ICH.

No MeSH data available.


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IL-1β expression and its cellular localization after ICH.(a) IL-1β expression in the peri-hematomal region and its cellular localization after ICH. The rat brains were fixed at 24 h after ICH and the peri-hematomal areas were double-immunostained with anti-IL-1β and anti-GFAP, anti-Iba1, anti-MAP2 or anti-MPO. IL-1β expression was co-localized with GFAP+ and MAP2+ cells, but not observed in MPO+ or Ibal1+ cells in the peri-hematomal area. White arrows show the co-localization of IL-1β with GFAP+ and MAP2+ cells, respectively. The scale bar represents 20 μm. (b) IL-1β expression in the central core of the bleeding area is shown. The rat brains were fixed at 24 h after ICH and the core bleeding areas were double-immunostained with anti-IL-1β and anti-GFAP, anti-Iba1, anti-MAP2 or anti-MPO. The scale bars represent 20 μm. There were almost no GFAP+ and MAP2+ cells and few iba1+ cells within the hematomal area. IL-1β expression was mostly co-localized with MPO+ cells in the peri-hematomal area. White arrows show the co-localization of IL-1β with Iba1+ and MPO+ cells, respectively.
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f5: IL-1β expression and its cellular localization after ICH.(a) IL-1β expression in the peri-hematomal region and its cellular localization after ICH. The rat brains were fixed at 24 h after ICH and the peri-hematomal areas were double-immunostained with anti-IL-1β and anti-GFAP, anti-Iba1, anti-MAP2 or anti-MPO. IL-1β expression was co-localized with GFAP+ and MAP2+ cells, but not observed in MPO+ or Ibal1+ cells in the peri-hematomal area. White arrows show the co-localization of IL-1β with GFAP+ and MAP2+ cells, respectively. The scale bar represents 20 μm. (b) IL-1β expression in the central core of the bleeding area is shown. The rat brains were fixed at 24 h after ICH and the core bleeding areas were double-immunostained with anti-IL-1β and anti-GFAP, anti-Iba1, anti-MAP2 or anti-MPO. The scale bars represent 20 μm. There were almost no GFAP+ and MAP2+ cells and few iba1+ cells within the hematomal area. IL-1β expression was mostly co-localized with MPO+ cells in the peri-hematomal area. White arrows show the co-localization of IL-1β with Iba1+ and MPO+ cells, respectively.

Mentions: In the present study, we observed that IL-1β immunoreactivity was almost completely restricted to reactive astrocytes and neurons in the peri-hematomal regions at 24 h after ICH (Fig. 5a). The immunoreactivity of IL-1β in astrocytes was merged with that of GFAP, whereas the immunoreactivity of IL-1β in neurons was merged with DAPI staining. These findings suggested that the IL-1β localizations in astrocytes and neurons were cytosolic and nuclear, respectively. There were no IL-1β-positive cells in the Iba1- or MPO-positive populations. We frequently observed IL-1β+ astrocytic processes surrounding and embracing blood vessels in the peri-hematomal region (Supplementary Fig. S5).


Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats
IL-1β expression and its cellular localization after ICH.(a) IL-1β expression in the peri-hematomal region and its cellular localization after ICH. The rat brains were fixed at 24 h after ICH and the peri-hematomal areas were double-immunostained with anti-IL-1β and anti-GFAP, anti-Iba1, anti-MAP2 or anti-MPO. IL-1β expression was co-localized with GFAP+ and MAP2+ cells, but not observed in MPO+ or Ibal1+ cells in the peri-hematomal area. White arrows show the co-localization of IL-1β with GFAP+ and MAP2+ cells, respectively. The scale bar represents 20 μm. (b) IL-1β expression in the central core of the bleeding area is shown. The rat brains were fixed at 24 h after ICH and the core bleeding areas were double-immunostained with anti-IL-1β and anti-GFAP, anti-Iba1, anti-MAP2 or anti-MPO. The scale bars represent 20 μm. There were almost no GFAP+ and MAP2+ cells and few iba1+ cells within the hematomal area. IL-1β expression was mostly co-localized with MPO+ cells in the peri-hematomal area. White arrows show the co-localization of IL-1β with Iba1+ and MPO+ cells, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5385548&req=5

f5: IL-1β expression and its cellular localization after ICH.(a) IL-1β expression in the peri-hematomal region and its cellular localization after ICH. The rat brains were fixed at 24 h after ICH and the peri-hematomal areas were double-immunostained with anti-IL-1β and anti-GFAP, anti-Iba1, anti-MAP2 or anti-MPO. IL-1β expression was co-localized with GFAP+ and MAP2+ cells, but not observed in MPO+ or Ibal1+ cells in the peri-hematomal area. White arrows show the co-localization of IL-1β with GFAP+ and MAP2+ cells, respectively. The scale bar represents 20 μm. (b) IL-1β expression in the central core of the bleeding area is shown. The rat brains were fixed at 24 h after ICH and the core bleeding areas were double-immunostained with anti-IL-1β and anti-GFAP, anti-Iba1, anti-MAP2 or anti-MPO. The scale bars represent 20 μm. There were almost no GFAP+ and MAP2+ cells and few iba1+ cells within the hematomal area. IL-1β expression was mostly co-localized with MPO+ cells in the peri-hematomal area. White arrows show the co-localization of IL-1β with Iba1+ and MPO+ cells, respectively.
Mentions: In the present study, we observed that IL-1β immunoreactivity was almost completely restricted to reactive astrocytes and neurons in the peri-hematomal regions at 24 h after ICH (Fig. 5a). The immunoreactivity of IL-1β in astrocytes was merged with that of GFAP, whereas the immunoreactivity of IL-1β in neurons was merged with DAPI staining. These findings suggested that the IL-1β localizations in astrocytes and neurons were cytosolic and nuclear, respectively. There were no IL-1β-positive cells in the Iba1- or MPO-positive populations. We frequently observed IL-1β+ astrocytic processes surrounding and embracing blood vessels in the peri-hematomal region (Supplementary Fig. S5).

View Article: PubMed Central - PubMed

ABSTRACT

As one of the most lethal stroke subtypes, intracerebral hemorrhage (ICH) is acknowledged as a serious clinical problem lacking effective treatment. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. High mobility group box-1 (HMGB1) is a ubiquitous and abundant nonhistone DNA-binding protein, and is also an important proinflammatory molecule once released into the extracellular space from the nuclei. Here, we show that treatment with neutralizing anti-HMGB1 mAb (1 mg/kg, i.v. twice) remarkably ameliorated ICH-injury induced by local injection of collagenase IV in the striatum of rats. Administration of anti-HMGB1 mAb inhibited the release of HMGB1 into the extracellular space in the peri-hematomal region, reduced serum HMGB1 levels and decreased brain edema by protecting blood-brain barrier integrity, in association with decreased activated microglia and the expression of inflammation-related factors at 24 h after ICH. Consequently, anti-HMGB1 mAb reduced the oxidative stress and improved the behavioral performance of rats. These results strongly indicate that HMGB1 plays a critical role in the development of ICH-induced secondary injury through the amplification of plural inflammatory responses. Intravenous injection of neutralizing anti-HMGB1 mAb has potential as a novel therapeutic strategy for ICH.

No MeSH data available.


Related in: MedlinePlus