An NLRP3 inflammasome inhibitor evoked dose-dependent anti-allodynia in the hindpaws of a rat model of chemotherapy-induced peripheral neuropathy.

Patients receiving chemotherapy for cancer treatment may develop chemotherapy-induced peripheral neuropathy (CIPN), a type of neuropathic (nerve) pain that is often difficult to treat. First-line analgesic/adjuvant agents recommended for the treatment of neuropathic pain often lack efficacy and/or evoke dose-limiting side-effects in patients with CIPN. Hence, there is a large unmet medical need for novel, well-tolerated analgesics for improving the relief of CIPN. As NLRP3 inflammasome activation is implicated in the pathobiology of CIPN, our aim was to assess the pain relief efficacy of a small molecule NLRP3 inflammasome inhibitor (MCC950), for the relief of CIPN in a rat model. Sprague-Dawley rats received four doses of cisplatin at once-weekly intervals. Temporal development of mechanical allodynia was documented in the bilateral hindpaws using von Frey filaments over a 4-week period after the first cisplatin dose. Rats with fully developed mechanical allodynia in the hindpaws received single oral doses of MCC950 (10-300 mg/kg), pregabalin (30 mg/kg) or vehicle. Hindpaw withdrawal thresholds were assessed pre-dose and at multiple times over a 4 h post-dosing period to produce PWT versus time curves. Single doses of MCC950 evoked dose-dependent anti-allodynia in the hindpaws, with the peak effect observed at 2-3 h post-dose. The mean effective dose 50% (ED50; 95% confidence intervals) of MCC950 was 56.2 mg/kg (21.8-150.7 mg/kg). On a molar basis, oral pregabalin was ~ 20% more potent than MCC950 in this model. In conclusion, NLRP3 inflammasome inhibitors are worthy of further investigation as novel treatments for CIPN.