Clostridium perfringens epsilon toxin induces permanent neuronal degeneration and behavioral changes

WINSTON E. MORRIS, JORGE GOLDSTEIN, LEANDRO M. REDONDO, ADRIANA CANGELOSI, PATRICIA GEOGHEGAN, MARCELA BROCCO; FABIAN LOIDL; MARIANO E. FERNANDEZ-MIYAKAWA

TOXICON

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2017

0041-0101

Clostridium perfringens epsilon toxin (ETX), the most potent toxin produced by thisbacteria, plays a key role in the pathogenesis of enterotoxaemia in ruminants, causing brainedema and encephalomalacia. Studies of animals suffering from ETX intoxication describe severe neurological disorders that are thought to be the result of vasogenic brain edemas38 and indirect neuronal toxicity, killing oligodendrocytes but not astrocytes, microglia, or39 neurons in vitro. In this study, by means of intravenous and intracerebroventricular delivery40 of sub-lethal concentrations of ETX, the histological and ultrastructural changes of the41 brain were studied in rats and mice. Histological analysis showed degenerative changes in42 neurons from the cortex, hippocampus, striatum and hypothalamus. Ultrastructurally,43 necrotic neurons and apoptotic cells were observed in these same areas, among axons with44 accumulation of neurofilaments and demyelination as well as synaptic stripping. Lesions45 observed in the brain after sub-lethal exposure to ETX, result in permanent behavioral46 changes in animals surviving ETX exposure, as observed individually in several animals47 and assessed in the Inclined Plane Test and the Wire Hang Test. Pharmacological studies48 showed that dexamethasone and reserpine but not ketamine or riluzole were able to reduce49 the brain lesions and the lethality of ETX. Cytotoxicity was not observed upon neuronal50 primary cultures in vitro. Therefore, we hypothesize that ETX can affect the brain of51 animals independently of death, producing changes on neurons or glia as the result of52 complex interactions, independently of ETX-BBB interactions.