title: Involvement of high mobility group box 1 in the development and maintenance of chemotherapy-induced peripheral neuropathy in rats.
abstract: Given that high mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, promotes nociception, we asked if inactivation of HMGB1 prevents or reverses chemotherapy-induced painful neuropathy in rats and also examined possible involvement of Toll-like receptor 4 (TLR4) and the receptor for advanced glycation endproduct (RAGE), known as targets for HMGB1. Painful neuropathy was produced by repeated i.p. administration of paclitaxel or vincristine in rats. Nociceptive threshold was determined by the paw pressure method and/or von Frey test in the hindpaw. Tissue protein levels were determined by immunoblotting. Repeated i.p. administration of the anti-HMGB1-neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, prevented the development of hyperalgesia and/or allodynia induced by paclitaxel or vincristine in rats. A single i.p. or intraplantar (i.pl.) administration of the antibody or rhsTM reversed the chemotherapy-induced neuropathy. A single i.pl. administration of a TLR4 antagonist or low molecular weight heparin, known to inhibit RAGE, attenuated the hyperalgesia caused by i.pl. HMGB1 and also the chemotherapy-induced painful neuropathy. Paclitaxel or vincristine treatment significantly decreased protein levels of HMGB1 in the dorsal root ganglia, but not sciatic nerves. HMGB1 thus participates in both development and maintenance of chemotherapy-induced painful neuropathy, in part through RAGE and TLR4. HMGB1 inactivation is considered useful to prevent and treat the chemotherapy-induced painful neuropathy.
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly Kinki University), Higashi-Osaka 577-8502, Japan; Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly Kinki University), Higashi-Osaka 577-8502, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Tsubota
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly Kinki University), Higashi-Osaka 577-8502, Japan.
authors.forename: Yudai
authors.initials: Y
authors.lastname: Kawaishi
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly Kinki University), Higashi-Osaka 577-8502, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamanishi
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly Kinki University), Higashi-Osaka 577-8502, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Kamitani
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly Kinki University), Higashi-Osaka 577-8502, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiguchi
authors.affiliation: Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ishikura
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 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 and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly Kinki University), Higashi-Osaka 577-8502, Japan. Electronic address: kawabata@phar.kindai.ac.jp.
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics / Q000517:prevention & control; D008297:Male; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects*; D010146:Pain / Q000139:chemically induced / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics* / Q000628:therapy; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: C000593874:Ager protein, rat; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D000067759:Receptor for Advanced Glycation End Products; D011994:Recombinant Proteins; C546931:THBD protein, human; D018180:Thrombomodulin; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014750:Vincristine; D017239:Paclitaxel
keywords: Chemotherapy-induced painful neuropathy; High mobility group box 1; Neuropathic pain; Thrombomodulin