Objective: Identification and evaluation of the potential of a novel NLR family pyrin domain containing 3 (NLRP3) inflammasome inhibitor (ZYIL1) as a Parkinson’s disease (PD) modifier.

Background: PD is the second most common neurodegenerative disorder after Alzheimer’s disease that affects approximately seven million people globally. Recently it’s becoming more and more evident that activation of the NLRP3 inflammasome signaling underlies pathogenesis of PD^1,2.

Method: ZYIL1 was rationally designed to be a potent & selective inhibitor of NLRP3 inflammasome. The potency and efficacy of ZYIL1 was evaluated in cell-based assays and in vivo animal models. THP-1 cells and isolated mouse microglial cells were primed with LPS and triggered either with ATP or Nigeracin. The cells were then treated with ZYIL1 and IL-1β levels were measured. Pharmacokinetic studies were conducted to determine level of ZYIL1 in the circulation and CSF of rodents and in non human primates. In C57 BL6J mice, LPS was administered intracranially and suppression of IL-1b was measured upon oral administration of ZYIL1. The pharmacodynamic effect of ZYIL1 was evaluated in 6-OHDA and MPTP-induced models of PD where immunohistochemistry was performed to measure the levels of tyrosine hydroxylase (TH) and α synuclein and neuro-behavioral parameters were assessed to evaluate improvement in motor function.

Results: ZYIL1 was found to be a potent NLRP3 inhibitor with IC₅₀ of 13nM and 43nM in THP1 cells and microglial cells respectively. Upon oral dosing (10mg/kg), CSF and plasma levels of ZYIL1  crossed the IC₅₀ level demonstrating brain penetration. ZYIL1 inhibited LPS- stimulated cytokine production in the brain upon oral dosing. In 6-OHDA and MPTP models of PD, ZYIL1 increased tyrosine hydroxylase levels and decrease α synuclein levels in the substantia niagra. It also improved motor function.

Conclusion: These findings indicate that ZYIL1 appears to have the potential for development as a therapeutic option for PD.

References: 1. Pike, A. F. et al. -Synuclein evokes NLRP3 inflammasome-mediated IL-1 secretion from primary human microglia. Glia 69, (2021).
2. Gordon, R. et al. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med 10, (2018).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-zyil1-a-novel-nlr-family-pyrin-domain-containing-3-protein-inhibitor-a-potential-disease-modifier-in-parkinsons-disorder/