Pharmacological inhibition of the NLRP3 inflammasome as a potential target for multiple sclerosis induced central neuropathic pain
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−1, 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−1 day−1), 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−1 day−1) did not differ significantly (P > 0.05) from the corresponding hindpaw PWTs for the sham (control) group. In addition, MCC950 at 50 mg kg−1 day−1 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.
KeywordsAnalgesia Experimental autoimmune encephalomyelitis Neuropathic pain Multiple sclerosis Paw withdrawal threshold (PWT) Relapsing–remitting experimental autoimmune encephalomyelitis (RR-EAE)
Central neuropathic pain
NOD-like receptor (NLR) family pyrin domain-containing protein 3
Paw withdrawal threshold
Relapsing–remitting experimental autoimmune encephalomyelitis
This work was supported by an Australian Research Council (ARC) Linkage Grant [LP120200623] and by a National Health and Medical Research Council (NHMRC) Grant [APP1059239]. The authors also acknowledge the Queensland Government Smart State Research Programme for supporting CIPDD research infrastructure. CIPDD is also supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We also gratefully acknowledge Avril A.B. Robertson for formulating MCC950 and Ruby Pelingon and Mark Butler for conducting the LC-MS/MS of MCC950 in RR-EAE-mouse plasma samples at the Institute for Molecular Bioscience (IMB), The University of Queensland, Australia.
NK and AK contributed to the research design and performance of the in vivo experiments. NK performed the data analysis of the in vivo experiments and drafted the manuscript; DB performed in vitro experiments and the associated data analysis. The study was conceived and supervised by MS and MC. All authors edited, read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
Professor Matt Cooper is CEO and a shareholder in Inflazome Ltd. This company is developing drugs to address clinical unmet needs in inflammatory disease by targeting inflammasomes. All other authors have no conflicts of interest.
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