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.
['Khan|Nemat|N|', 'Kuo|Andy|A|', 'Brockman|David A|DA|', 'Cooper|Matthew A|MA|', 'Smith|Maree T|MT|']
D000818:Animals D004195:Disease Models, Animal D004681:Encephalomyelitis, Autoimmune, Experimental D005260:Female D006614:Hindlimb D006930:Hyperalgesia D058847:Inflammasomes D051379:Mice D008810:Mice, Inbred C57BL D009103:Multiple Sclerosis D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D009437:Neuralgia
Multiple sclerosis Neuropathic pain Paw withdrawal threshold (PWT) Analgesia Experimental autoimmune encephalomyelitis Relapsing–remitting experimental autoimmune encephalomyelitis (RR-EAE)