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

Rosaria Pascente, Federica Frigerio, Massimo Rizzi, Luca Porcu, Marina Boido, Joe Davids, Malik Zaben, Daniele Tolomeo, Marta Filibian, William P. Gray, Annamaria Vezzani, Teresa Ravizza

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)146-155
Number of pages10
JournalNeurobiology of Disease
Volume93
DOIs
Publication statusPublished - Sep 1 2016

Keywords

  • Astrocytes
  • Biomarker
  • Comorbidities
  • Epileptogenesis
  • Hippocampus
  • Imaging
  • Learning and memory
  • Status epilepticus

ASJC Scopus subject areas

  • Neurology

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  • Cite this

    Pascente, R., Frigerio, F., Rizzi, M., Porcu, L., Boido, M., Davids, J., Zaben, M., Tolomeo, D., Filibian, M., Gray, W. P., Vezzani, A., & Ravizza, T. (2016). Cognitive deficits and brain myo-Inositol are early biomarkers of epileptogenesis in a rat model of epilepsy. Neurobiology of Disease, 93, 146-155. https://doi.org/10.1016/j.nbd.2016.05.001