title: Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats.
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.
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Dengli
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Keyue
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Wake
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Teshigawara
authors.affiliation: School of Pharmacy, Shujitsu University, Okayama, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D001930:Brain Injuries / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*; D002543:Cerebral Hemorrhage / Q000097:blood / Q000150:complications*; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000097:blood; D007249:Inflammation / Q000097:blood / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D017208:Rats, Wistar; D014661:Vasoconstriction
chemical_list: D000911:Antibodies, Monoclonal; D051401:Aquaporin 4; D024243:HMGB1 Protein; D053583:Interleukin-1beta