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

Abstract

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.

Effect of Porcine Clostridium perfringens on Intestinal Barrier, Immunity, and Quantitative Analysis of Intestinal Bacterial Communities in Mice

“…Some studies in broilers presented the same results in intestinal morphology ( 34 – 37 ). Other studies found that the C. perfringens enterotoxin (CPE), which is the main toxin produced by C. perfringens type A, displayed a dose-dependent effect and CPE can induce the intestinal injury ( 38 – 40 ). These studies focused on the toxaemic outcome of toxin absorption from the intestine into the circulation, and they did not adequately examine the specific changes that occur during C. perfringens infection.…”

Pathologic findings on ruminant enteric clostridial diseases reveal specificities and differences among iota and iota-like toxins

“…Enterotoxemia caused by the action of ITX presents similarities between intestinal lesions and lesions caused by toxins from other strains of C. perfringens, which makes it difficult to apply the protocol used for enterotoxemia caused by C. perfringens type D. In addition, there are cross-reactions between ITX and iota-like toxins that make it difficult to determine the specificity of ITX in lesions (Uzal, 2004;Navarro et al, 2019).…”

“…C. perfringens strains can cause intestinal infections, including enteritis and enterotoxemia due to the action of toxins in the intestine of infected animals and/or other organs (Sayeed et al, 2008). Toxin action has resulted in skin, subcutaneous and muscle tissue diseases, gas gangrene or malignant edema, most of which are mediated by one or more toxins produced by C. perfringens (Uzal et al, 2010;Freedman et al, 2015;Brandi et al, 2016) (Songer, 1996;Songer and Miskimmins, 2004;Navarro et. al., 2019).…”

“…Alone each component is not toxic, but combined, Ia and Ib are cytotoxic to multiple cells (Sakurai et al, 2009;Uzal et al, 2018;Mehdizadeh-Gohari et al, 2021). The specificity and participation of ITX in enteric diseases and its effects in the intestine are still not completely elucidated (Navarro et al, 2019). However, recent histological and immunohistochemical results obtained from sections of the jejunum and ileum have contributed to a better understanding of the mechanism of action of ITX and other toxins.…”

“…These diseases are mediated by one or more toxins from C. perfringens (Uzal et al, 2016). Among the enteric infections associated with C. perfringens, the type C strains have been confirmed to affect humans and animals (Uzal et al, 2016), whereas other toxin types were described to cause disease in humans or animals individually (Navarro et al, 2019). The virulence of C. perfringens is largely attributed to its ability to produce a variety of different extracellular enzymes and toxins (Table 1).…”