title: Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy.
abstract: One major unmet clinical need in epilepsy is the identification of therapies to prevent or arrest epilepsy development in patients exposed to a potential epileptogenic insult. The development of such treatments has been hampered by the lack of non-invasive biomarkers that could be used to identify the patients at-risk, thereby allowing to design affordable clinical studies. Our goal was to test the predictive value of cognitive deficits and brain astrocyte activation for the development of epilepsy following a potential epileptogenic injury. We used a model of epilepsy induced by pilocarpine-evoked status epilepticus (SE) in 21-day old rats where 60-70% of animals develop spontaneous seizures after around 70days, although SE is similar in all rats. Learning was evaluated in the Morris water-maze at days 15 and 65 post-SE, each time followed by proton magnetic resonance spectroscopy for measuring hippocampal myo-Inositol levels, a marker of astrocyte activation. Rats were video-EEG monitored for two weeks at seven months post-SE to detect spontaneous seizures, then brain histology was done. Behavioral and imaging data were retrospectively analysed in epileptic rats and compared with non-epileptic and control animals. Rats displayed spatial learning deficits within three weeks from SE. However, only epilepsy-prone rats showed accelerated forgetting and reduced learning rate compared to both rats not developing epilepsy and controls. These deficits were associated with reduced hippocampal neurogenesis. myo-Inositol levels increased transiently in the hippocampus of SE-rats not developing epilepsy while this increase persisted until spontaneous seizures onset in epilepsy-prone rats, being associated with a local increase in S100β-positive astrocytes. Neuronal cell loss was similar in all SE-rats. Our data show that behavioral deficits, together with a non-invasive marker of astrocyte activation, predict which rats develop epilepsy after an acute injury. These measures have potential clinical relevance for identifying individuals at-risk for developing epilepsy following exposure to epileptogenic insults, and consequently, for designing adequately powered antiepileptogenesis trials.
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Pascente
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Frigerio
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rizzi
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Porcu
authors.affiliation: Neuroscience Institute "Cavalieri Ottolenghi", Department of Neuroscience, University of Torino, Torino, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Boido
authors.affiliation: Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Davids
authors.affiliation: Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Malik
authors.initials: M
authors.lastname: Zaben
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Tolomeo
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Filibian
authors.affiliation: Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: William P
authors.initials: WP
authors.lastname: Gray
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy. Electronic address: teresa.ravizza@marionegri.it.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ravizza
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000503:physiopathology*; D060825:Cognitive Dysfunction / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D008297:Male; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000150:complications / Q000503:physiopathology*
keywords: Astrocytes; Biomarker; Comorbidities; Epileptogenesis; Hippocampus; Imaging; Learning and memory; Status epilepticus