活性化protein Cはproteinase-activated receptor 1 を介して神経障害性疼痛を抑制する

• Published in: 日本薬理学会年会要旨集 p. 1-B-SS08-3
• Main Authors: 圓尾, 賢悟, 池田, 裕哉, 坪田, 真帆, 王, 登莉, 西堀, 正洋, 南, 達郎, 伊藤, 彰敏, 川畑, 篤史
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: anticoagulant; pain; peripheral nervous system
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.96.0_1-B-SS08-3

The prevention of oxaliplatin-induced peripheral neuropathy (OIPN) by thrombomodulin alfa (TMα) involves thrombin-dependent activation of protein C (PC) and thrombin-activatable fibrinolysis inhibitor (TAFI), in addition to inactivation of high mobility group box 1 (HMGB1). We have demonstrated that complement C5a, degradable by activated TAFI (TAFIa), known as carboxypeptidase B (CPB), is involved in OIPN development. In the present study, we examined the effect of APC on OIPN as well as surgically induced neuropathic pain in mice, and asked whether proteinase-activated receptor 1 (PAR1) would participate in the effects of APC in those neuropathic pain models, given that APC is an unbiased or biased agonist of PAR1. The OIPN in mice was prevented fully by TMα, an anti-HMGB1-neutralizing antibody (HAb) or TAFIa/CPB, and, to a lesser extent, by APC. Vorapaxar, a PAR1 antagonist, completely and partially canceled the anti-OIPN effects of APC and TMα, respectively. Interestingly, the neuropathic allodynia caused by partial sciatic nerve ligation was also abolished by TMα, and reduced by HAb or APC, and the effect of APC was reversed by vorapaxar. Our data suggest that PAR1 is involved in the preventive effects of APC and, in part, of TMα on OIPN and surgically induced neuropathic pain.