Involvement of high mobility group box 1 in the development and maintenance of chemotherapy-induced peripheral neuropathy in rats

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• 作者：Takeshi Nishida^a ; ^b ; ¹ ; Maho Tsubota^a ; ¹ ; Yudai Kawaishi^a ; Hiroki Yamanishi^a ; Natsuki Kamitani^a ; Fumiko Sekiguchi^a ; Hiroyasu Ishikura^b ; Keyue Liu^c ; Masahiro Nishibori^c ; Atsufumi Kawabata^a ; ^{kawabata@phar.kindai.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; ^{takeiteasyatsufumi@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：APC ; activated protein C ; CBP ; cyclic-AMP regulatory element binding protein (CREB)-binding protein ; DIC ; disseminated intravascular coagulation ; DRG ; dorsal root ganglia ; GAPDH ; glyceraldehyde-3-phosphoate dehydrogenase ; HAT ; histone acetyltransferase ; HDAC ; histone deacetylase ; HMGB1 ; high mobility group box 1 ; i.pl. ; intraplantar ; LPS-RS ; lipopolysaccharide from Rhodobacter sphaeroides ; LMWH ; low molecular weight heparin ; PCAF ; p300/CBP-associated factor ; RAGE ; receptor for advanced glycation
• 刊名：Toxicology
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：365
• 期：Complete
• 页码：48-58
• 全文大小：3453 K

文摘

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.