The Potential Therapeutic Agent Mepacrine Protects Caco-2 Cells against Clostridium perfringens Enterotoxin Action

Freedman, John C.; Hendricks, Matthew R.; McClane, Bruce A.

doi:10.1128/msphere.00352-17

Cited by 9 publications

(15 citation statements)

References 46 publications

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“…An early study suggested that the agent mepacrine is a candidate CPE therapeutic since it interfered with CPE-induced electrophysiologic activity in artificial lipid bilayers (35). A more recent study demonstrated that mepacrine is also able to protect enterocyte-like Caco-2 cells from CPE action in vitro (31). This protection did not involve mepacrine inactivating the CPE protein; instead, this drug interfered with the formation of CPE pores and with the activity of pores already present on CPE-treated Caco-2 cells (31).…”

Section: Discussionmentioning

confidence: 99%

“…The CH-1 pore complex is required for CPE to cause Caco-2 cell cytotoxicity (29,31,37). In previous studies, we showed that the prolonged presence of mepacrine can reduce CH-1 levels present in Caco-2 cells by increasing CPE monomer dissociation from membranes prior to oligomerization (31). Therefore, an experiment was performed to assess whether mepacrine affects CH-1 levels in vivo.…”

Section: Effects Of Mepacrine On Ch-1 Formation In the Small Intestinementioning

confidence: 99%

“…In an in vitro model using pure synthetic lipid bilayers, the presence of mepacrine was shown to decrease CPE-induced electrophysiologic activity (35). More recently, it was demonstrated that mepacrine also reduces CPE-induced cytotoxicity in enterocyte-like Caco-2 cells in vitro (31). This protection involved at least two mechanisms: (i) the reduction of CPE pore formation by increasing the dissociation of CPE monomers and (ii) the inhibition of CPE pore activity (31).…”

mentioning

confidence: 99%

“…In the same way, Caco-2 cells and small intestinal loops in rabbits can be protected against CPE using a peptide corresponding to the second extracellular loop sequence of claudin-4 as a receptor decoy (29,30). However, the potential use of those synthetic peptides as therapeutic tools is limited considering their high cost and likely inactivation in the gastrointestinal tract (31).…”

mentioning

confidence: 99%

“…More recently, it was demonstrated that mepacrine also reduces CPE-induced cytotoxicity in enterocyte-like Caco-2 cells in vitro (31). This protection involved at least two mechanisms: (i) the reduction of CPE pore formation by increasing the dissociation of CPE monomers and (ii) the inhibition of CPE pore activity (31). The effective therapeutic use of mepacrine in other intestinal infections, coupled with its ability to protect enterocyte-like cells in vitro from CPE action, provides justification for in vivo investigation of this drug as a potential therapeutic agent against CPE in vivo.…”

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confidence: 99%

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Potential Therapeutic Effects of Mepacrine against Clostridium perfringens Enterotoxin in a Mouse Model of Enterotoxemia

et al. 2019

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Clostridium perfringens enterotoxin (CPE) is a pore-forming toxin that causes the symptoms of common bacterial food poisoning and several non-foodborne human gastrointestinal diseases, including antibiotic-associated diarrhea and sporadic diarrhea. In some cases, CPE-mediated disease can be very severe or fatal due to the involvement of enterotoxemia. Therefore, the development of potential therapeutics against CPE action during enterotoxemia is warranted. Mepacrine, an acridine derivative drug with broad-spectrum effects on pores and channels in mammalian membranes, has been used to treat protozoal intestinal infections in human patients. A previous study showed that the presence of mepacrine inhibits CPE-induced pore formation and activity in enterocyte-like Caco-2 cells, reducing the cytotoxicity caused by this toxin in vitro. Whether mepacrine is similarly protective against CPE action in vivo has not been tested. When the current study evaluated whether mepacrine protects against CPEinduced death and intestinal damage using a murine ligated intestinal loop model, mepacrine protected mice from the enterotoxemic lethality caused by CPE. This protection was accompanied by a reduction in the severity of intestinal lesions induced by the toxin. Mepacrine did not reduce CPE pore formation in the intestine but inhibited absorption of the toxin into the blood of some mice. Protection from enterotoxemic death correlated with the ability of this drug to reduce CPE-induced hyperpotassemia. These in vivo findings, coupled with previous in vitro studies, support mepacrine as a potential therapeutic against CPE-mediated enterotoxemic disease.

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Section: Discussionmentioning

confidence: 99%

Section: Effects Of Mepacrine On Ch-1 Formation In the Small Intestinementioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Potential Therapeutic Effects of Mepacrine against Clostridium perfringens Enterotoxin in a Mouse Model of Enterotoxemia

et al. 2019

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The effects of probiotic Bacillus coagulans on the cytotoxicity and expression of alpha toxin gene of Clostridium perfringens type A

et al. 2019

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Evaluation of the inflammatory response to Kudoa septempunctata genotype ST3 isolated from olive flounder (Paralichthys olivaceus) in Caco-2 cells

Ahn

Ko²,

Kim

et al. 2018

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Kudoa septempunctata (Myxosporea, Multivalvulida) is a parasite of the trunk muscle of cultured olive flounder (Paralichthys olivaceus). We investigated whether K. septempunctata genotype ST3 spores induce cell damage and the secretion of inflammatory mediators in Caco-2 cells, which exhibit characteristics similar to human intestinal epithelial cells. Purified K. septempunctata spores were heated at 95 °C for 5 min. Lactate dehydrogenase (LDH) release was measured to determine the efficacy of denaturation. Naïve and heated spores, lipopolysaccharide (positive control) and vehicle (negative control) were added to Caco-2 cells. Cells were subjected to the cytotoxic LDH assay and western blot analysis to examine the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. Supernatants were collected to measure nitric oxide (NO) and prostaglandin E2 (PGE2). Most spores were denaturated by heating, and the spore morphology was found to be wrinkled with shell valves and polar capsules. In addition, cytotoxicity and inflammatory mediators, such as NO, PGE2, iNOS, and COX-2, remained unchanged in Caco-2 cells following exposure to naïve and heated spores compared with the positive controls. Collectively, the findings of this study imply that spores of K. septempunctata genotype ST3 do not cause inflammation in Caco-2 cells.

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The Potential Therapeutic Agent Mepacrine Protects Caco-2 Cells against Clostridium perfringens Enterotoxin Action

Cited by 9 publications

References 46 publications

Potential Therapeutic Effects of Mepacrine against Clostridium perfringens Enterotoxin in a Mouse Model of Enterotoxemia

Potential Therapeutic Effects of Mepacrine against Clostridium perfringens Enterotoxin in a Mouse Model of Enterotoxemia

The effects of probiotic Bacillus coagulans on the cytotoxicity and expression of alpha toxin gene of Clostridium perfringens type A

Evaluation of the inflammatory response to Kudoa septempunctata genotype ST3 isolated from olive flounder (Paralichthys olivaceus) in Caco-2 cells

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