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Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy

Pascente, Rosaria, Frigerio, Federica, Rizzi, Massimo, Porcu, Luca, Boido, Marina, Davids, Joe, Zaben, Malik ORCID:, Tolomeo, Daniele, Filibian, Marta, Gray, William P. ORCID:, Vezzani, Annamaria and Ravizza, Teresa 2016. Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy. Neurobiology of Disease 93 , pp. 146-155. 10.1016/j.nbd.2016.05.001

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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 70 days, 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Publisher: Elsevier
ISSN: 0969-9961
Date of First Compliant Deposit: 16 May 2018
Date of Acceptance: 5 May 2016
Last Modified: 06 Nov 2023 18:38

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