1. Academic Validation
  2. Flufenamic acid protects against intestinal fluid secretion and barrier leakage in a mouse model of Vibrio cholerae infection through NF-κB inhibition and AMPK activation

Flufenamic acid protects against intestinal fluid secretion and barrier leakage in a mouse model of Vibrio cholerae infection through NF-κB inhibition and AMPK activation

  • Eur J Pharmacol. 2017 Mar 5;798:94-104. doi: 10.1016/j.ejphar.2017.01.026.
Pawin Pongkorpsakol 1 Saravut Satitsri 2 Preedajit Wongkrasant 2 Pamorn Chittavanich 3 Suticha Kittayaruksakul 4 Potjanee Srimanote 5 Varanuj Chatsudthipong 2 Chatchai Muanprasat 6
Affiliations

Affiliations

  • 1 Graduate Program in Translational Medicine, Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand.
  • 2 Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand.
  • 3 Department of Pharmacology, Faculty of Science, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand.
  • 4 Department of Basic Medical Science, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Thailand.
  • 5 Graduate Studies, Faculty of Allied Health Science, Thammasat University, Paholyothin Road, Rangsit, Prathumthani 12120, Thailand.
  • 6 Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand; Excellent Center for Drug Discovery, Mahidol University, Rama VI Road, Rajathevi, Bangkok 10400, Thailand. Electronic address: chatchai.mua@mahidol.ac.th.
Abstract

Nuclear factor kappa B (NF-κB)-mediated inflammatory responses play crucial roles in the pathogenesis of diarrhea caused by the Vibrio cholerae El Tor variant (EL), which is a major Bacterial strain causing recent cholera outbreaks. Flufenamic acid (FFA) has previously been demonstrated to be a potent activator of AMP-activated protein kinase (AMPK), which is a negative regulator of NF-κB signaling. This study aimed to investigate the anti-diarrheal efficacy of FFA in a mouse model of EL Infection and to investigate the mechanisms by which FFA activates AMPK in intestinal epithelial cells (IEC). In a mouse closed loop model of EL Infection, FFA treatment (20mg/kg) significantly abrogated EL-induced intestinal fluid secretion and barrier disruption. In addition, FFA suppressed NF-κB nuclear translocation and expression of proinflammatory mediators and promoted AMPK phosphorylation in the EL-infected mouse intestine. In T84 cells, FFA induced AMPK activation. Furthermore, FFA promoted tight junction assembly and prevented interferon gamma (IFN-γ)-induced barrier disruption in an AMPK-dependent manner. Biochemical and molecular docking analyses indicated that FFA activates AMPK via a direct stimulation of calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ) activity. Collectively, our data indicate that FFA represents a class of existing drugs that may be of potential utility in the treatment of cholera caused by EL Infection via AMPK-mediated suppression of NF-κB signaling in IEC.

Keywords

AMP-activated protein kinase; Cholera; Flufenamic acid; Inflammation; Vibrio cholerae.

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