title: Glycyrrhizin inhibits traumatic brain injury by reducing HMGB1-RAGE interaction.
abstract: Glycyrrhizin (GL) is a major constituent of licorice root and has been suggested to inhibit the release of high mobility group box-1 (HMGB1), a protein considered representative of damage-associated molecular patterns. We found that GL bound HMGB1 but not RAGE with a moderate equilibrium dissociation constant value based on surface plasmon resonance analysis. This complex formation prevented HMGB1 from binding to RAGE in vitro. The effects of glycyrrhizin on traumatic brain injury (TBI) induced by fluid percussion were examined in rats or mice in the present study. GL was administered intravenously after TBI. Treatment of rats with GL dose-dependently suppressed the increase in BBB permeability and impairment of motor functions, in association with the inhibition of HMGB1 translocation in neurons in injured sites. The beneficial effects of GL on motor and cognitive functions persisted for 7 days after injury. The expression of TNF-α, IL-1β and IL-6 in injured sites was completely inhibited by GL treatment. In RAGE-/- mice, the effects of GL were not observed. These results suggested that GL may be a novel therapeutic agent for TBI through its interference with HMGB1 and RAGE interaction.
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan; Department of Neurosurgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Okuma
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Keyue
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Wake
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Hui
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Teshigawara
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan; Department of Neurosurgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Haruma
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Neurosurgery, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Date
authors.affiliation: Department of Pharmacology, Kinki University, Osakasayama 589-8511, Japan.
authors.forename: Hideo K
authors.initials: HK
authors.lastname: Takahashi
authors.affiliation: Department of Pharmacology, School of Pharmacy, Shujitsu University, Okayama 703-8516, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. Electronic address: yakuri@md.okayama-u.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011897:Random Allocation; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C104200:Hbp1 protein, rat; D018696:Neuroprotective Agents; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019695:Glycyrrhizic Acid
keywords: Brain edema; Glycyrrhizin; HMGB1; RAGE; Traumatic brain injury