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. 2021 Sep 27;10(10):2550. doi: 10.3390/cells10102550

Figure 2.

Figure 2

Prevention and reversal of the CIPN caused by bortezomib by thrombomodulin alfa, and the role of endogenous thrombin. (A,B) Preventive (A) or therapeutic (B) effects of thrombomodulin alfa on the CIPN caused by bortezomib in mice. Bortezomib at 0.4 mg/kg or vehicle was administered i.p. on days 0, 2, 5, 7, 9, and 12. The mice received repeated i.p. administration of thrombomodulin alfa at 1 or 3 mg/kg, 30 min before each dose of bortezomib (A), or a single i.p. administration of thrombomodulin alfa at 1, 3, or 10 mg/kg after the establishment of CIPN on day 14 (B). (C,D) Cancellation of the anti-CIPN effect of TMα by argatroban, a thrombin inhibitor. The mice received repeated i.p. administration of argatroban at 10 mg/kg, 30 min before each administration of thrombomodulin alfa at 10 mg/kg (60 min before each administration of bortezomib at 0.4 mg/kg) (C). (E,F) Long-term inhibition of endogenous thrombin by argatroban promotes the CIPN (E) and increased plasma HMGB1 levels (F) in mice treated with bortezomib at 0.1 mg/kg, a subeffective dose. The mice received repeated i.p. administration of argatroban at 10 mg/kg once a day on days 0–13 after the onset of treatment with bortezomib. Plasma HMGB1 levels were determined after the measurement of nociceptive threshold on day 14 (F). Data show the mean with S.E.M for 4–6 (A), 5–6 (B), 5 (D), 9–13 (E), or 9–11 (F) mice. V, vehicle; BTZ, bortezomib; TMα, thrombomodulin alfa; AT, argatroban. * p < 0.05, ** p < 0.01 vs. V in V-treated mice (A,B,E,F) or V + V in V-treated mice (D). † p < 0.05, †† p < 0.01 vs. V in BTZ-treated mice (A,B,E,F) or V + V in BTZ-treated mice (D). # p < 0.05, ## p < 0.01 vs. V + TMα in BTZ-treated mice (D).