Journal
INFLAMMOPHARMACOLOGY
Volume 26, Issue 1, Pages 77-86Publisher
SPRINGER BASEL AG
DOI: 10.1007/s10787-017-0401-9
Keywords
Analgesia; Experimental autoimmune encephalomyelitis; Neuropathic pain; Multiple sclerosis; Paw withdrawal threshold (PWT); Relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE)
Categories
Funding
- Australian Research Council (ARC) [LP120200623]
- National Health and Medical Research Council (NHMRC) [APP1059239]
- Therapeutic Innovation Australia (TIA)
- Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program
- Australian Research Council [LP120200623] Funding Source: Australian Research Council
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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 similar to 1 h post-dosing with a duration of action of similar to 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.
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