Abstract
Microarray profiling was used to investigate gene expression in the hypoxic seizure model of acquired epilepsy in the rat, with the aim of characterizing functional pathways which are persistently activated or repressed during epileptogenesis. Hippocampal and cortical tissues were transcriptionally profiled over a one week period following an initial series of seizures induced by mild hypoxia at post-natal day 10 (P10), and the gene expression data was then analyzed with a focus on gene set enrichment analysis, an approach which emphasizes regulation of entire pathways rather than of individual genes. Animals were subjected to one of three conditions: a control with no hypoxia, hypoxic seizures, and hypoxic seizures followed by treatment with the AMPAR antagonist NBQX, a compound currently proposed to be a modulator of epileptogenesis. While temporal gene expression in the control samples was found to be consistent with known processes of neuronal maturation in the rat for the given time window, the hypoxic seizure response was found to be enriched for components of the PI3K/mTOR and Wnt signaling pathways, alongside gene sets representative of glutamatergic, synaptic and axonal processes, perhaps regulated as a downstream consequence of activation of these pathways. Wnt signaling components were also found enriched in the more specifically epileptogenic NBQX-responsive gene set. While activation of the mTOR pathway is consistent with its known role in epileptogenesis and strengthens the case for mTOR or PI3K pathway inhibitors as potential anti-epileptogenic drugs, investigation of the role of Wnt signaling and the effect of appropriate inhibitors might offer a parallel avenue of research toward anti-epileptogenic treatment of epilepsy.
Highlights
Epilepsy is a widespread neurological disorder affecting as many as 3% of all individuals at some point in their lives, with about 30% of chronic epileptic patients refractory to drugs, and with many patients experiencing apparently progressive forms of the disease [1]
While historically attention has been focused on controlling the acute symptoms of the disease, more recently emphasis has been placed on understanding the underlying process of epileptogenesis, that is, the molecular and structural changes that occur in brain tissue, sometimes over extended periods of time of months or years, and which eventually lead to the epileptic state [2]
The hypoxic seizure response gene set is enriched in Wnt and mTOR pathway components We examined the set of genes with persistent changes in expression post-hypoxia, relative to the baseline normoxic conditions, these genes defining the ‘‘hypoxic seizure (HS) response set’’
Summary
Epilepsy is a widespread neurological disorder affecting as many as 3% of all individuals at some point in their lives, with about 30% of chronic epileptic patients refractory to drugs, and with many patients experiencing apparently progressive forms of the disease [1]. While historically attention has been focused on controlling the acute symptoms of the disease, more recently emphasis has been placed on understanding the underlying process of epileptogenesis, that is, the molecular and structural changes that occur in brain tissue, sometimes over extended periods of time of months or years, and which eventually lead to the epileptic state [2] This new ‘‘disease-modifying’’ focus might eventually provide for a more rational approach to treatment of the disorder, in which one deals with the underlying condition rather than just its symptoms, and concomitantly may reveal a greater number and variety of molecular targets for intervention than the ones currently affected by known anti-epileptic drugs. While recent profiling studies have more appropriately addressed epileptogenic processes [10,11,12], identifying genes regulated in chronic or longer-term settings, a multiplicity of models will doubtless be required for understanding of the mechanisms underlying epileptogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
