, 1999; Uzal and Kelly, 1997; Uzal et al., 1997) or direct attack of

neural cells constituting brain tissue remains matter of debate. This review aims to summarize ET effects on the nervous system (mainly the central nervous system) and focuses on the causal linkage between symptoms or manifestations expressed by intoxicated animals as well as structures affected, and the potential direct effect of ET on neural cells. C. perfringens (also termed Clostridium welchii) is a Gram-positive, anaerobic and spore-forming bacillus. C. perfringens is a ubiquitous environmental bacterium that can be found as normal microflora component of soil, dust and sediments. As many click here other Clostridia, it grows in cadavers and litter. Spores are ingested and can reach intestines of various vertebrates ( McClane and Chakrabarti, 2004). Overall, C. perfringens is considered as a normal inhabitant of the gastro intestinal tract. Typically, perturbation of microbial balance in the gut (for instance by a rapid change in diet) induces overgrowth

of C. perfringens leading to production of high level of toxins. Proliferation of types B and D in gut causes enterotoxaemia in sheep and goat and more rarely in cattle ( Uzal et al., 2002; McClane and Chakrabarti, 2004). The bacterium has also been found in pig ( Bergeland, 1972; Bergeland et al., 1966; Cho et al., 1991) and smaller renting animals, such as rabbit and chicken ( Heikinheimo and Korkeala, 2005; Sting, 2009). ET-producing GBA3 strains of C. perfringens have Caspase inhibitor been isolated from human intestine ( Gleeson-White and Bullen, 1955; Kohn and Warrack, 1955) and upon the occasion of a case of gas-gangrene ( Morinaga et al., 1965). However, it remains

unclear whether the strains isolated had a role in the disease observed in man. 17 different toxins including alpha, beta, iota and epsilon toxins are produced by various strains of C. perfringens. According to produced-toxins, C. perfringens have been divided into five main groups, from A through E ( Finegold, 1977; Fisher et al., 2006; Niilo, 1980). Only two groups of C. perfringens (types B and D) produce ET. C. perfringens type B produces ET together with alpha-and beta-toxins whereas type D produces ET, alpha-toxin and perfringolysin-O (reviewed by Alouf and Popoff, 2006; McClane et al., 2006; Uzal and Songer, 2008). ET is a single-chain protein synthesized as a protoxin of 32–33 kDa (McDonel, 1980). Removal of the 11 N-terminal (or the 13 N-terminal) and of the 29 C-terminal residues amino-acids by proteases (notably the α-chymotrypsin, trypsin and λ-protease) converts the inactive protoxin (proET) into a fully active form (i.e. the toxin, ET 28.6 kDa), with a lethal dose (LD) of about 70 ng kg−1 in mice (i.e. 400,000 mouse-LD per mg protein) (Minami et al., 1997; reviewed by Popoff, 2011a). Proteases involved in conversion of proET into ET are synthesized by C. perfringens ( Minami et al.