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Mefloquine targets NLRP3 to reduce lipopolysaccharide-induced systemic inflammation and neural injury

Si-Yuan Jiang1, Tian Tian1, Wen-Jie Li1

  • 1Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China.

EMBO Reports
|August 25, 2023
PubMed

Insights

Mefloquine, an antimalarial drug, effectively inhibits the NLRP3 inflammasome, a key factor in many diseases. This discovery offers a potential new treatment for inflammatory and neurological conditions like Parkinson's disease.

Area of Science:

  • Immunology
  • Pharmacology
  • Neuroscience

Background:

  • The NLRP3 inflammasome is implicated in numerous human diseases.
  • Current therapies targeting NLRP3 inflammasomes are limited due to safety and efficacy concerns.
  • Repurposing existing drugs offers a viable strategy for identifying NLRP3 inhibitors.

Purpose of the Study:

  • To identify selective and potent NLRP3 inflammasome inhibitors from FDA-approved drugs.
  • To investigate the therapeutic potential of identified inhibitors in disease models.

Main Methods:

  • Screening of an FDA-approved drug library to identify NLRP3 inhibitors.
  • Biochemical assays to determine mefloquine's binding site and inhibitory mechanism on NLRP3.
  • In vivo studies using mouse models of systemic inflammation and Parkinson's disease.

Main Results:

  • Mefloquine was identified as a highly selective and potent NLRP3 inhibitor.
  • Mefloquine directly binds to the NACHT and LRR domains of NLRP3, preventing its activation.
  • Mefloquine treatment ameliorated symptoms in mouse models of LPS-induced inflammation and Parkinson's disease-like pathology.

Conclusions:

  • Mefloquine is a promising therapeutic agent for NLRP3-driven diseases.
  • This study expands the potential clinical applications of mefloquine.
  • Repurposing mefloquine offers a novel strategy for treating inflammatory and neurodegenerative disorders.
Keywords:
NLRP3Parkinson's diseaseinflammationinhibitormefloquine

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