Centre for Integrated Preclinical Drug Development, UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
Inflammopharmacology. 2018 Feb;26(1):77-86. doi: 10.1007/s10787-017-0401-9. Epub 2017 Sep 30.
The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of multiple diseases including neuroinflammation associated with multiple sclerosis (MS). However, the extent to which NLRP3 has a pathobiological role in MS-associated central neuropathic pain (CNP) is unknown. Hence, the present study was designed to address this issue using an optimised relapsing-remitting experimental encephalomyelitis (RR-EAE)-mouse model of MS-associated neuropathic pain. RR-EAE mice with fully developed mechanical allodynia in the bilateral hindpaws (paw withdrawal thresholds (PWTs) ≤ 1 g) at day 16 post-immunisation (p.i.) were administered single oral bolus doses of MCC950, a selective and potent small-molecule inhibitor of NLRP3, once daily for 21 consecutive days. Following administration of the first dose of MCC950 at 50 mg kg, the mean (± SEM) peak anti-allodynic effect was observed at ~ 1 h post-dosing with a duration of action of ~ 2 h. Following chronic dosing with MCC950, mechanical allodynia in the bilateral hindpaws was progressively reversed by oral treatment with MCC950 (50 mg kg day), but not vehicle. Specifically, by day 25 p.i. and continuing until study completion on day 36 p.i., bilateral hindpaw PWTs of RR-EAE mice treated with MCC950 (50 mg kg day) did not differ significantly (P > 0.05) from the corresponding hindpaw PWTs for the sham (control) group. In addition, MCC950 at 50 mg kg day attenuated disease relapses in RR-EAE mice indicated by tail limpness as well as hindlimb weakness. Together, our findings suggest that inhibition of NLRP3 inflammasome activation may be a potential therapeutic approach to alleviate MS-associated CNP and disease relapses in patients with RR-MS.
NOD 样受体 (NLR) 家族包含 pyrin 结构域的蛋白 3 (NLRP3) 炎症小体与多种疾病的发病机制有关，包括多发性硬化症 (MS) 相关的神经炎症。然而，NLRP3 在 MS 相关中枢性神经病理性疼痛 (CNP) 中的病理生物学作用程度尚不清楚。因此，本研究旨在使用优化的复发缓解型实验性自身免疫性脑脊髓炎 (RR-EAE)-MS 相关神经性疼痛小鼠模型来解决这一问题。在免疫后第 16 天（p.i.），双侧后爪机械性痛觉过敏完全发展（双侧后爪缩足阈值（PWTs）≤1g）的 RR-EAE 小鼠，每日单次口服给予 MCC950，一种选择性和有效的 NLRP3 小分子抑制剂，连续 21 天。在给予 MCC950 第一剂后 50mg/kg，观察到约 1 小时时出现峰值抗痛觉过敏作用，作用持续时间约 2 小时。在慢性给予 MCC950 后，MCC950（50mg/kg/天）的口服治疗逐渐逆转双侧后爪的机械性痛觉过敏，但载体无此作用。具体来说，在 RR-EAE 小鼠 p.i. 第 25 天，并持续到 p.i. 第 36 天研究结束时，接受 MCC950（50mg/kg/天）治疗的 RR-EAE 小鼠双侧后爪 PWTs 与假手术（对照）组的相应后爪 PWTs 无显著差异（P>0.05）。此外，MCC950（50mg/kg/天）还可减轻 RR-EAE 小鼠的疾病复发，表现为尾巴无力和后肢无力。总之，我们的研究结果表明，抑制 NLRP3 炎症小体的激活可能是缓解 MS 相关 CNP 和 RR-MS 患者疾病复发的一种潜在治疗方法。
