Review: Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesis

Abstract

A. J. Becker (2018) Neuropathology and Applied Neurobiology 44, 112-129 Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesisIn many patients who suffer from epilepsies, recurrent epileptic seizures do not start at birth but develop later in life. This holds particularly true for epilepsies with a focal seizure origin including focal cortical dysplasias and temporal lobe epilepsy (TLE). TLE most frequently has its seizure onset in the hippocampal formation. Hippocampal biopsies of pharmacoresistant TLE patients undergoing epilepsy surgery for seizure control most frequently reveal the damage pattern of hippocampal sclerosis, that is, segmental neuronal cell loss and concomitant astrogliosis. Many TLE patients report on transient brain insults early in life, which is followed by a 'latency' period lacking seizure activity of months or even years before chronic recurrent seizures start. The plethora of structural and cellular mechanisms that convert the hippocampal formation to become chronically hyperexcitable after a transient insult to the brain are summarized under the term epileptogenesis. In contrast to the obstacles arising for experimental studies of epileptogenesis aspects in human surgical hippocampal tissue, recent animal model approaches allow insights into mechanisms of epileptogenesis. Relevant models of transient brain insults in this context comprise several distinct types of lesions including excitoxic status epilepticus (SE), electrical seizure induction, traumatic brain injury, induction of inflammatory processes by hyperthermia and viral inflammation and others. In pathogenetic terms, aberrant transcriptional and epigenetic reprogramming, acquired channel-and synaptopathies, neuronal network and blood-brain barrier dysfunction as well as innate and adaptive immunitymediated damage play major roles. In subsequent steps, respective animal models have been used in order to test whether this dynamic process can be either retarded or even abolished by interfering with epileptogenic mechanisms. Well-controlled subsequent analyses of epileptogenic cascades characterized in animal models using carefully stratified human hippocampal biopsies to exploit the unique opportunities given by these rare and precious brain tissue samples aim to translate into novel antiepileptogenic approaches. Respective preclinical tests can open entirely new perspectives for tailor-made treatments in patients with the potential to avoid the emergence of chronic focal seizure events.

The antiepileptic effect of Gastrodiae Rhizoma through modulating overexpression of mTOR and attenuating astrogliosis in pilocarpine mice model

“…The degree of lesion in the hippocampus is associated with neuronal loss and astrogliosis that correlated with seizure severity. that astrocytic dysfunction would strengthen the release of glutamate and intensify Wetherington et al demonstrated neuronal excitability, thus leading to seizures . Our results illustrated that mice with fewer seizures had less severe neuronal atrophy and astrogliosis in their hippocampus and the hilus of DG, implying that GR could modulate SE formation and contribute to seizure maintenance.…”

“…that astrocytic dysfunction would strengthen the release of glutamate and intensify Wetherington et al demonstrated neuronal excitability, thus leading to seizures. [24][25][26] Our results illustrated that mice with fewer F I G U R E 3 A, The regulatory effect of Gastrodiae Rhizoma (GR) and carbamazepine (CBZ) on p-mTOR expression. Data were shown as mean ± SD; negative absorbance was not excluded from the analysis.…”

Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis

“…The theory of "master regulators" controlling the transcriptional dynamics of genes involved in epileptogenesis is attractive because this would mean that blocking these transcriptional regulators could be particularly powerful in exerting antiepileptogenic and disease-modifying effects. Numerous "master regulator candidates," comprising transcriptional activators and repressors, have been suggested (for review, see Becker, 2018). However, only few reports so far have demonstrated the regulation of more than one gene encoding a protein integrally involved in the processes underlying epileptogenesis by a single transcription factor (TF) (McClelland et al, 2014).…”

FV18 Towards epileptogenesis staging with deep neural networks

“…Studying early EPG in human patients is extremely difficult, simply because the epilepsy is typically only detected after the FSS. Therefore, work on early EPG is typically restricted to animal models [4]. Furthermore, early EPG can comprise a complex cascade of changes to the brain after the initial brain insult and this cascade may strongly depend on the type of brain insult.…”