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

NEUROBIOLOGY OF DISEASE

卷:93

Article

Pascente, Rosaria¹  Frigerio, Federica¹  Rizzi, Massimo¹  Porcu, Luca²  Boido, Marina³  Davids, Joe⁴  Zaben, Malik⁴  Tolomeo, Daniele¹  Filibian, Marta^1,5  Gray, William P.⁴  Vezzani, Annamaria¹  Ravizza, Teresa¹ 

[1] IRCCS Ist Ric Farmacol Mario Negri, Dept Neurosci, Milan, Italy

[2] IRCCS Ist Ric Farmacol Mario Negri, Dept Oncol, Milan, Italy

[3] Univ Turin, Dept Neurosci, Neurosci Inst Cavalieri Ottolenghi, Turin, Italy

[4] Cardiff Univ, Sch Med, Neurosci & Mental Hlth Res Inst, Cardiff, S Glam, Wales

[5] Univ Pavia, Dept Phys, Pavia, Italy

关键词: Biomarker;    Epileptogenesis;    Imaging;    Comorbidities;    Learning and memory;    Astrocytes;    Hippocampus;    Status epilepticus;   

DOI  :  10.1016/j.nbd.2016.05.001

来源: Elsevier

【 摘 要 】

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 S100 beta-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. (C) 2016 Elsevier Inc. All rights reserved.

【 授权许可】

Free