Chemotherapy-induced peripheral neuropathy caused by vincristine involves high mobility group box 1 (HMGB1) released from macrophages and Schwann cells

Vincristine (VCR), an anticancer drug, frequently causes chemotherapy-induced peripheral neuropathy (CIPN). We have reported that macrophages (Mφ)-derived HMGB1 is involved in CIPN induced by paclitaxel in mice, whereas the mechanisms for VCR-induced CIPN (VIPN) remain unclear. We thus examined whether VIPN involves HMGB1 derived from Mφ or Schwann cells in mice. VCR at 0.2 mg/kg was administrated i.p. to mice daily for 10 days with a 2-day break, and nociceptive threshold at the hindpaw was evaluated by von Frey test. An anti-HMGB1-neutralizing antibody (HMGB1-Ab), soluble thrombomodulin (TMα) capable of inactivating HMGB1, and ethyl pyruvate (EP), known to inhibit HMGB1 release from Mφ, were administered i.p. 1 h before each dose of VCR. Liposomal clodronate (Cld), a Mφ depletor, was administered i.p. twice on days 4 and 6 during VCR treatment. Mφ accumulation in the sciatic nerve was determined by immunofluorescent staining. HMGB1 release from mouse Mφ-like RAW264.7 (RAW) cells and primary rat Schwann cells (SC) was evaluated by Western blotting. Repeated administration of VCR markedly decreased nociceptive threshold, an effect reversed by treatment with HMGB1-Ab, TMα, EP or Cld. The number of perineural Mφ in the sciatic nerve significantly increased in VCR-treated mice. Stimulation with VCR at 100 nM and 10 nM caused HMGB1 release from Mφ-like RAW cells and SC, respectively. Our data suggest that HMGB1 released from Mφ and SC contributes to the development of VIPN in mice.