Role of non-macrophage cell-derived HMGB1 in oxaliplatin-induced peripheral neuropathy and its prevention by the thrombin/thrombomodulin system in rodents: negative impact of anticoagulants

Abstract

BackgroundMacrophage-derived high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, plays a key role in the development of chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel in rodents. Endothelial thrombomodulin (TM) promotes thrombin-induced degradation of HMGB1, and TMα, a recombinant human soluble TM, abolishes peripheral HMGB1-induced allodynia in mice. We thus examined whether HMGB1, particularly derived from macrophages, contributes to oxaliplatin-induced neuropathy in mice and analyzed the anti-neuropathic activity of the TM/thrombin system.MethodsCIPN models were created by the administration of oxaliplatin in mice and rats, and the nociceptive threshold was assessed by von Frey test or paw pressure test. Macrophage-like RAW264.7 cells were stimulated with oxaliplatin in vitro. Proteins were detected and/or quantified by Western blotting, immunostaining, or enzyme-linked immunosorbent assay.ResultsIntraperitoneal administration of an anti-HMGB1-neutralizing antibody (AB) at 1 mg/kg prevented the oxaliplatin-induced allodynia in mice and rats. Antagonists of Toll-like receptor (TLR) 4, receptor for advanced glycation end products (RAGE) and CXCR4 among the HMGB1-targeted pro-nociceptive receptors, also mimicked the anti-neuropathic activity of AB in mice. Macrophage accumulation in the sciatic nerve was observed in mice treated with paclitaxel, but not oxaliplatin, and neither macrophage depletion nor inhibitors of macrophage activation affected oxaliplatin-induced allodynia. Oxaliplatin was 10- to 100-fold less potent than paclitaxel in releasing HMGB1 from macrophage-like RAW264.7 cells. Like AB, TMα at 10 mg/kg prevented the oxaliplatin-induced allodynia in mice as well as rats, an effect abolished by argatroban at 10 mg/kg, a thrombin inhibitor. The anti-neuropathic activity of TMα in oxaliplatin-treated mice was suppressed by oral anticoagulants such as warfarin at 1 mg/kg, dabigatran at 75 mg/kg, and rivaroxaban at 10 mg/kg, but not antiplatelet agents such as aspirin at 50 mg/kg and clopidogrel at 10 mg/kg. Repeated administration of the anticoagulants gradually developed neuropathic allodynia and elevated plasma HMGB1 levels in mice treated with a subeffective dose of oxaliplatin.ConclusionsOur data thus suggests a causative role of HMGB1 derived from non-macrophage cells in oxaliplatin-induced peripheral neuropathy and a thrombin-dependent anti-neuropathic activity of exogenous TMα and, most probably, endogenous TM.

A placebo-controlled, double-blind, randomized study of recombinant thrombomodulin (ART-123) to prevent oxaliplatin-induced peripheral neuropathy

“…An additional anti-inflammatory effect of ART-123 attributed to direct binding to high-mobility group box 1 protein (HMGB1) and enhancement of its degradation by thrombin has also been reported [19,20]. Recently, it has been reported that ART-123 prevented oxaliplatin-induced hyperalgesia and allodynia in animal models [21,22]. The animal study suggested that ART-123 prevents the development of sensory symptoms of OIPN through activation of TAFI and protein C without affecting the anti-tumor activity of oxaliplatin [21].…”

Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream H2S/Cav3.2 Signaling in Mice

“…HMGB1, a nuclear protein, once released to the extracellular space, plays a role as a damage-associated molecular pattern (DAMP) or alarmin protein, and promotes not only inflammation [4,5], but also pain signals [6]. Extracellular HMGB1 in the peripheral tissue is considered to participate in inflammatory and neuropathic pain through direct or indirect activation of RAGE, Toll-like receptor 4 (TLR4) or CXCR4 [2,[7][8][9][10]. We have demonstrated that the activation of RAGE by HMGB1 derived from unknown cells plays a role in the development of the bladder pain accompanying CPA-induced cystitis in mice [2].…”

Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy

“…Finally, the identification of reliable biomarkers able to predict the clinical course of OIPN would represent a relevant improvement in the clinical research toolkit. Currently, measurement of the level of neurofilament light chains in plasma or serum samples seems to be the most promising candidate based on preclinical evidence obtained using different neurotoxic chemotherapy regimens [55,56], but further validation in the clinical setting is required.…”