A novel selective NLRP3 inhibitor shows disease-modifying potential in animal models of Parkinson’s disease

Abstract

Pathological activation of the Nod-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome signaling underlies many autoimmune and neuroinflammatory conditions. Here we report that, a rationally designed, novel, orally active, selective NLRP3 inflammasome inhibitor, ZYIL1, showed potent inhibition of ATP, Nigericin and monosodium urate-mediated interleukin (IL)-1β release in THP-1 cells and human PBMC. In isolated microglia cells, the IC50 of ZYIL1 mediated inhibition of IL-1β was 43 nM. ZYIL1 displayed good pharmacokinetic profile in mice, rats and primates after oral administration and the concentrations found in the brain and cerebrospinal fluid (CSF) were markedly higher than the IC50 values. In an in vivo model of neuroinflammation, ZYIL1 demonstrated robust suppression of NLRP3 inflammasome activation and IL-1β upon oral administration. This translated into efficacy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (6-OHDA)-induced Parkinson’s disease (PD) models in mice. In MPTP and/or 6-OHDA models, treatment with ZYIL1 ameliorated motor deficits, degeneration of nigrostriatal dopaminergic neurons and abnormal accumulation of α-synuclein. There were positive changes in the genes related to walking, locomotor activity, neurogenesis, neuroblast proliferation and neuronal differentiation in the PD brain indicating improvement in neural health which translated into improved mobility. These findings clearly indicate that selective NLRP3 inhibitor ZYIL1, ameliorates neuroinflammation and appears to have the potential for disease modification and progression associated with PD.