Proof-of-concept that network pharmacology is effective to modify development of acquired temporal lobe epilepsy
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (levetiracetam and topiramate) for which in silico analysis of drug-protein interaction networks indicated a synergistic effect on a large functional network of epilepsy-relevant proteins. Using the intrahippocampal kainate mouse model of temporal lobe epilepsy, the drug combination was administered during the latent period before onset of spontaneous recurrent seizures (SRS). When SRS were periodically recorded by video-EEG monitoring after termination of treatment, a significant decrease in incidence and frequency of SRS was determined, indicating antiepileptogenic efficacy. Such efficacy was not observed following single drug treatment. Furthermore, a combination of levetiracetam and phenobarbital, for which in silico analysis of drug-protein interaction networks did not indicate any significant drug-drug interaction, was not effective to modify development of epilepsy. Surprisingly, the promising antiepileptogenic effect of the levetiracetam/topiramate combination was obtained in the absence of any significant neuroprotective or anti-inflammatory effects as indicated by multimodal brain imaging and histopathology. High throughput RNA-sequencing (RNA-seq) of the ipsilateral hippocampus of mice treated with the levetiracetam/topiramate combination showed that several genes that have been linked previously to epileptogenesis, were significantly differentially expressed, providing interesting entry points for future mechanistic studies. Overall, we have discovered a novel combination treatment with promise for prevention of epilepsy.
Date Issued
2020-02-01
Date Acceptance
2019-10-30
Citation
Neurobiology of Disease, 2020, 134, pp.1-16
ISSN
0969-9961
Publisher
Elsevier
Start Page
1
End Page
16
Journal / Book Title
Neurobiology of Disease
Volume
134
Copyright Statement
© 2019 Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Sponsor
Commission of the European Communities
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31678583
PII: S0969-9961(19)30339-0
Grant Number
602102
Subjects
Blood-brain barrier leakage
Epileptogenesis
Kainate
Levetiracetam
Multimodal brain imaging
Neurodegeneration
Neuroinflammation
RNA-seq
Seizures
Topiramate
Publication Status
Published
Coverage Spatial
United States
Article Number
ARTN 104664
Date Publish Online
2019-11-01