Mafenide derivatives inhibit neuroinflammation in Alzheimer's disease by regulating pyroptosis

Area of Science:

• Neuroinflammation
• Immunology
• Pharmacology

Background:

• Pyroptosis is a pro-inflammatory cell death pathway.
• Gasdermin D (GSDMD) cleavage by Caspase-1 is the primary execution mechanism.
• Mafenide previously showed inhibitory effects on pyroptosis via GSDMD-Asp275 site.

Purpose of the Study:

• To develop novel GSDMD cleavage inhibitors based on the sulfonamide structure.
• To evaluate the efficacy of synthesized compounds against pyroptosis in vitro and in vivo.
• To explore new therapeutic strategies for neuroinflammation.

Main Methods:

• Synthesis of sulfonamide derivatives (Sulfa-4, Sulfa-20).
• In vitro screening in BV2 and iBMDM cell lines to assess pyroptosis inhibition.
• In vivo studies in APP/PS1 mice to evaluate neuroinflammation effects.
• Biochemical assays including immunoprecipitation and biotin-labeled assays to confirm target binding.

Main Results:

• Five synthesized compounds demonstrated superior pyroptosis inhibition compared to mafenide.
• Sulfa-4 and Sulfa-22 significantly reduced microglial activation and inflammatory factors in neuroinflammation models.
• These compounds suppressed GSDMD cleavage, NLRP3 inflammasome, and Caspase-1 expression.
• Sulfa-4 and Sulfa-22 confirmed direct binding to GSDMD protein.

Conclusions:

• Sulfa-4 and Sulfa-22 are potent inhibitors of GSDMD cleavage, offering a new mechanism to suppress pyroptosis.
• These compounds show therapeutic potential for neuroinflammatory diseases.
• This research provides a foundation for developing novel anti-inflammatory drugs targeting GSDMD.