title: CNF1 Enhances Brain Energy Content and Counteracts Spontaneous Epileptiform Phenomena in Aged DBA/2J Mice.
abstract: Epilepsy, one of the most common conditions affecting the brain, is characterized by neuroplasticity and brain cell energy defects. In this work, we demonstrate the ability of the Escherichia coli protein toxin cytotoxic necrotizing factor 1 (CNF1) to counteract epileptiform phenomena in inbred DBA/2J mice, an animal model displaying genetic background with an high susceptibility to induced- and spontaneous seizures. Via modulation of the Rho GTPases, CNF1 regulates actin dynamics with a consequent increase in spine density and length in pyramidal neurons of rat visual cortex, and influences the mitochondrial homeostasis with remarkable changes in the mitochondrial network architecture. In addition, CNF1 improves cognitive performances and increases ATP brain content in mouse models of Rett syndrome and Alzheimer's disease. The results herein reported show that a single dose of CNF1 induces a remarkable amelioration of the seizure phenotype, with a significant augmentation in neuroplasticity markers and in cortex mitochondrial ATP content. This latter effect is accompanied by a decrease in the expression of mitochondrial fission proteins, suggesting a role of mitochondrial dynamics in the CNF1-induced beneficial effects on this epileptiform phenotype. Our results strongly support the crucial role of brain energy homeostasis in the pathogenesis of certain neurological diseases, and suggest that CNF1 could represent a putative new therapeutic tool for epilepsy.
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Roma, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Travaglione
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Roma, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ballan
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Roma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fortuna
authors.affiliation: Institute of Cellular Biology and Neurobiology, CNR, Via del Fosso di Fiorano 64/65, 00143, Roma, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferri
authors.affiliation: Department of Veterinary Public Health and Food Safety, Viale Regina Elena 299, 00161, Roma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Guidotti
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Campana
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Roma, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Fiorentini
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Roma, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Loizzo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D029968:Escherichia coli Proteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D012640:Seizures / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D001427:Bacterial Toxins; D015415:Biomarkers; D029968:Escherichia coli Proteins; C060296:cytotoxic necrotizing factor type 1; D000255:Adenosine Triphosphate