title: Clostridium perfringens epsilon toxin induces permanent neuronal degeneration and behavioral changes.
abstract: Clostridium perfringens epsilon toxin (ETX), the most potent toxin produced by this bacteria, plays a key role in the pathogenesis of enterotoxaemia in ruminants, causing brain edema and encephalomalacia. Studies of animals suffering from ETX intoxication describe severe neurological disorders that are thought to be the result of vasogenic brain edemas and indirect neuronal toxicity, killing oligodendrocytes but not astrocytes, microglia, or neurons in vitro. In this study, by means of intravenous and intracerebroventricular delivery of sub-lethal concentrations of ETX, the histological and ultrastructural changes of the brain were studied in rats and mice. Histological analysis showed degenerative changes in neurons from the cortex, hippocampus, striatum and hypothalamus. Ultrastructurally, necrotic neurons and apoptotic cells were observed in these same areas, among axons with accumulation of neurofilaments and demyelination as well as synaptic stripping. Lesions observed in the brain after sub-lethal exposure to ETX, result in permanent behavioral changes in animals surviving ETX exposure, as observed individually in several animals and assessed in the Inclined Plane Test and the Wire Hang Test. Pharmacological studies showed that dexamethasone and reserpine but not ketamine or riluzole were able to reduce the brain lesions and the lethality of ETX. Cytotoxicity was not observed upon neuronal primary cultures in vitro. Therefore, we hypothesize that ETX can affect the brain of animals independently of death, producing changes on neurons or glia as the result of complex interactions, independently of ETX-BBB interactions.
authors.affiliation: Instituto de Patobiología, Centro Nacional de Investigaciones Agropecuarias, Instituto Nacional de Tecnología Agropecuaria, Calle Las Cabañas y Los Reseros s/n, Casilla de Correo 25 (1686), Hurlingham, Buenos Aires, Argentina. Electronic address: morris.winston@inta.gob.ar.
authors.forename: Winston E
authors.initials: WE
authors.lastname: Morris
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Ciudad Autónoma de Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Rivadavia 1917 (1033), Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: jogol@fmed.uba.ar.
authors.forename: Jorge
authors.initials: J
authors.lastname: Goldstein
authors.affiliation: Instituto de Patobiología, Centro Nacional de Investigaciones Agropecuarias, Instituto Nacional de Tecnología Agropecuaria, Calle Las Cabañas y Los Reseros s/n, Casilla de Correo 25 (1686), Hurlingham, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Rivadavia 1917 (1033), Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: redondo.leandro@inta.gob.ar.
authors.forename: Leandro M
authors.initials: LM
authors.lastname: Redondo
authors.affiliation: Centro Nacional de Control de Calidad de Biológicos, ANLIS "Dr. Carlos G. Malbrán", Av. Vélez Sarsfield 563, C1282AFF, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: acangelosi@anlis.gov.ar.
authors.forename: Adriana
authors.initials: A
authors.lastname: Cangelosi
authors.affiliation: Centro Nacional de Control de Calidad de Biológicos, ANLIS "Dr. Carlos G. Malbrán", Av. Vélez Sarsfield 563, C1282AFF, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: pgeoghegan@anlis.gov.ar.
authors.forename: Patricia
authors.initials: P
authors.lastname: Geoghegan
authors.affiliation: Instituto de Investigaciones Biotecnológicas, "Dr. Rodolfo A. Ugalde" IIB-INTECH UNSAM-CONICET, Av. 25 de Mayo y Francia, Campus Miguelete UNSAM, Edificio IIB-INTECH San Martín, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Rivadavia 1917 (1033), Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: mbrocco@iib.unsam.edu.ar.
authors.forename: Marcela
authors.initials: M
authors.lastname: Brocco
authors.affiliation: Instituto de Biología Celular y Neurociencias "Prof. E. De Robertis", Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Ciudad Autónoma de Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Rivadavia 1917 (1033), Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: floidl@fmed.uba.ar.
authors.forename: Fabián C
authors.initials: FC
authors.lastname: Loidl
authors.affiliation: Instituto de Patobiología, Centro Nacional de Investigaciones Agropecuarias, Instituto Nacional de Tecnología Agropecuaria, Calle Las Cabañas y Los Reseros s/n, Casilla de Correo 25 (1686), Hurlingham, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Rivadavia 1917 (1033), Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: fernandezmiyakawa.m@inta.gob.ar.
authors.forename: Mariano E
authors.initials: ME
authors.lastname: Fernandez-Miyakawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001427:Bacterial Toxins / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D003711:Demyelinating Diseases / Q000139:chemically induced; D003907:Dexamethasone / Q000627:therapeutic use; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D007031:Hypothalamus / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D007382:Intermediate Filaments / Q000187:drug effects; D007649:Ketamine / Q000627:therapeutic use; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000627:therapeutic use; D019782:Riluzole / Q000627:therapeutic use; D013569:Synapses / Q000187:drug effects
chemical_list: D001427:Bacterial Toxins; C039811:Clostridium perfringens epsilon-toxin; D018696:Neuroprotective Agents; D007649:Ketamine; D019782:Riluzole; D003907:Dexamethasone; D012110:Reserpine
keywords: Behavior; Brain; Clostridium perfringens; Enterotoxemia; Epsilon toxin; Neurodegeneration