INTERNATIONAL ASSOCIATION OF BIOMEDICAL SCIENCES

  “ IABS Forum-2023 ” December 2023
ABSTRACT

Novel Small-molecule Inhibitor of NLRP3 Inflammasome as Possible Treatment for Amyotrophic Lateral Sclerosis

Ariana Soares Dias Portela, Sibilla Masieri, Sean X. Naughton, Ruth Iban Arias, Eun-jeong Yang, Giulio Maria Pasinetti

Icahn School of Medicine at Mount Sinai

  ABSTRACT

  Objectives: The nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor protein 3 (NLRP3) inflammasome is over activated in neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS), leading to chronic inflammation by activating several cytokines. A novel small-molecule inhibitor C77 was described to block NLRP3 inflammasome, therefore our study is focused in optimizing and understanding the capabilities of the small-molecule inhibitor for possible treatment of ALS. We hypothesize that C77 can cross the BBB and the muscle, therefore blocking NLRP3 inflammasome and slow disease progression and mortality.
  Methods: WT mice were intraperitoneally injected 2 hours before LPS (0.5mg/kg) or 10% DMSO with Corn Oil (Vehicle) with C77 (50mg/kg; 30mg/kg; 10mg/kg) or the Vehicle. The mice were then sacrificed 2 hours after the second administration and brain and plasma were isolated. The left hemisphere cortex was used for a dose response ELISA assay and Western Blot to target IL-1β. Furthermore, a pharmacokinetics study was performed with 2 month old WT male mice with three different concentrations of the C77, 25mg/kg, 50mg/kg and 100 mg/kg. The drug was administrated by gavage and the animals where sacrificed 4h later. Brain, plasma, muscle and kidney were collected.
  Results: Mice treated with LPS and 50m/kg presented the lower amount of IL-1β in the cortex samples compared to the control group, furthermore in the pharmacokinetics study the C77 compound was shown to possibly cross the BBB by presenting a higher presence in the brain tissue at 50mg/kg and 100mg/kg, although not significant. Finally this compound showed a remarkable and significant presence in the muscle tissue.
  Conclusion: The study supports the hypothesis that C77 compound might be a novel possible treatment for ALS disease progression.

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