Related Experiment Video

Updated: Jul 31, 2025

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

9.2K

Dorzolamide suppresses PKCδ -TIRAP-p38 MAPK signaling axis to dampen the inflammatory response

Sajjan Rajpoot1, Ashutosh Kumar2, Vadim Gaponenko3

  • 1Department of Biosciences & Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India.

Future Medicinal Chemistry
|May 2, 2023
PubMed

Insights

Dorzolamide (DZD) disrupts the TIRAP-PKCδ interaction, a key pathway in sepsis immune dysfunction. This novel approach effectively reduces sepsis-related inflammation and organ impairment in mice.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Sepsis is a life-threatening condition characterized by dysregulated immune responses and organ dysfunction.
  • Macrophages are critical immune cells involved in the pathogenesis of sepsis.
  • Immune dysfunction in sepsis involves complex molecular signaling pathways.

Purpose of the Study:

  • To investigate the role of TIRAP-PKCδ interaction in macrophage activation during sepsis.
  • To identify and validate a therapeutic agent targeting the TIRAP-PKCδ interaction.

Main Methods:

  • Studied TIRAP-PKCδ interaction and downstream signaling in macrophages using Western blot and qRT-PCR.
  • Employed virtual screening to identify Dorzolamide (DZD) as an inhibitor of TIRAP-PKCδ interaction.
  • Validated DZD efficacy in vitro and in a mouse model of sepsis.

Main Results:

  • TIRAP-PKCδ interaction is essential for p38 MAPK activation and the expression of proinflammatory cytokines via NF-κB and AP-1.
  • Dorzolamide (DZD) significantly inhibited these sepsis-associated signaling pathways.
  • DZD treatment attenuated sepsis-induced inflammation and organ dysfunction in vivo.

Conclusions:

  • Targeting the TIRAP-PKCδ interaction represents a novel therapeutic strategy for sepsis.
  • Dorzolamide (DZD) shows promise as a potential treatment for sepsis by modulating key inflammatory pathways.
Keywords:
AP1NF-κBPKCδTIRAPdorzolamide (DZD)macrophagesp38 MAPKpro-inflammatory cytokinessepsis

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