Medicine (RMH) - Research Publications

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Author: O'Brien, Terence × End date: 2022 × Subject: Epileptogenesis ×

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    Early life maternal separation stress augmentation of limbic epileptogenesis: The role of corticosterone and HPA axis programming
    Koe, AS ; Salzberg, MR ; Morris, MJ ; O'Brien, TJ ; Jones, NC (PERGAMON-ELSEVIER SCIENCE LTD, 2014-04)
    Early life stress causes long-lasting effects on the limbic system that may be relevant to the development of mesial temporal lobe epilepsy (MTLE) and its associated psychopathology. Recent studies in rats suggest that maternal separation (MS), a model of early life stress, confers enduring vulnerability to amygdala kindling limbic epileptogenesis. However, the mechanisms underlying this remain unknown. Here, we tested whether hypothalamic-pituitary-adrenal (HPA) axis hyper-reactivity induced by MS - specifically the excessive secretion of corticosterone following a seizure - was involved in this vulnerability. In adult female rats subjected to MS from postnatal days 2-14, seizure-induced corticosterone responses were significantly augmented and prolonged for at least two hours post-seizure, compared to control early-handled (EH) rats. This was accompanied by reduced seizure threshold (p<0.05) and increased vulnerability to the kindling-induced progression of seizure duration (p<0.05) in MS rats. Pre-seizure treatment with the corticosterone synthesis inhibitor, metyrapone (MET) (50mg/kgsc) effectively blocked seizure-induced corticosterone responses. When delivered throughout kindling, MET treatment also reversed the MS-induced reduction in seizure threshold and the lengthened seizure duration back to levels of EH rats. These observations suggest that adverse early life environments induce a vulnerability to kindling epileptogenesis mediated by HPA axis hyper-reactivity, which could have relevance for the pathogenesis of MTLE.
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    Hypometabolism precedes limbic atrophy and spontaneous recurrent seizures in a rat model of TLE
    Jupp, B ; Williams, J ; Binns, D ; Hicks, RJ ; Cardamone, L ; Jones, N ; Rees, S ; O'Brien, TJ (WILEY, 2012-07)
    PURPOSE: Temporal hypometabolism on fluorodeoxyglucose positron emission tomography (FDG-PET) is a common finding in patients with drug-resistant temporal lobe epilepsy (TLE). The pathophysiology underlying the hypometabolism, including whether it reflects a primary epileptogenic process, or whether it occurs later as result of limbic atrophy or as a result of chronic seizures, remains unknown. This study aimed to investigate the ontologic relationship among limbic atrophy, histological changes, and hypometabolism in rats. METHODS: Serial in vivo imaging with FDG-PET and volumetric magnetic resonance imaging (MRI) was acquired before and during the process of limbic epileptogenesis resulting from kainic acid-induced status epilepticus in the rat. The imaging data were correlated with histologic measures of cell loss, and markers of astrogliosis (glial fibrillary acid protein [GFAP]), synaptogenesis (synaptophysin), glucose transporter 1 (Glut1) and energy metabolism (cytochrome oxidase C), on brains of the animals following the final imaging point. KEY FINDINGS: Hippocampal hypometabolism on FDG-PET was found to be present 24 h following status epilepticus, tending to lessen by 1 week and then become more marked again following the onset of spontaneous seizures. Atrophy of limbic structures was evident from 7 days post-SE, becoming progressively more marked on serial MRI over subsequent weeks. No relationship was observed between the severity of MRI-detected atrophy or CA1 pyramidal cell loss and the degree of the hypometabolism on FDG-PET. However, an inverse relationship was observed between hypometabolism and increased expression of the Glut1 and synaptophysin in the hippocampus. SIGNIFICANCE: These findings demonstrate that hypometabolism occurs early in the processes of limbic epileptogenesis and is not merely a consequence of pyramidal cell loss or the progressive atrophy of limbic brain structures that follow. The hypometabolism may reflect cellular mechanisms occurring early during epileptogenesis in addition to any effects of the subsequent recurrent spontaneous seizures.