Abstract
In the epilepsy spectrum, temporal lobe epilepsy (TLE) is the most common and devastating focal and symptomatic epilepsy form in adults, where more than 30% of patients develop pharmacoresistance. It is not fully understood how the gene expression contributes to establishing an epileptic phenotype. Cerebrovascular remodeling directed by VEGF (vascular endothelial growth factor) signaling might modulate the synaptic neurotransmission in the epileptic brain. To address this question, the gene expression was profiled in biopsies of the temporal cortex from diagnosed patients with pharmacoresistant TLE that underwent surgical resection to seizure control. One hundred sixty-eight genes related to VEGF signaling and GABA and glutamate neurotransmissions were evaluated. Genes related to downstream signaling —phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases (MAPK), and Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) pathways— and neurotransmitters metabolism were evaluated too. Thirty-nine genes were upregulated. The genes encoding for G protein q polypeptide, serine racemase, gephyrin, and glutamate/cystine antiporter system xCT appeared as novel upregulated genes in the pharmacoresistant TLE. ClueGO, a Cytoscape plugin, was used to build a gene network associated using Gene Ontology (GO) terminology. Enrichment analysis by ClueGO retrieves that positive regulation of endothelial cell proliferation, nerve development, and neuronal apoptosis were over-represented categories. In conclusion, VEGF signaling is confirmed as a relevant mediator in the pharmacoresistant TLE. In addition, the enrichment analysis applied to differentially expressed genes suggests new pharmacological targets to be assessed in the treatment of pharmacoresistant TLE. Results make up an approximation to better understand the epileptic brain and complement the available data.
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Abbreviations
- TLE:
-
Temporal lobe epilepsy
- HS:
-
Hippocampal sclerosis
- FCD:
-
Focal cortical dysplasia
- GABA:
-
Gamma-aminobutyric acid
- MAPK:
-
Mitogen-activated protein kinase
- CREB:
-
cAMP-responsive element-binding protein
- RT:
-
Retrotranscription
- qPCR:
-
Quantitative PCR
- VEGF:
-
Vascular endothelial growth factor
- PI3K:
-
Phosphoinositide 3-kinase
- JAK/STAT:
-
Janus-activated kinase/signal transducer and activator of transcription
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The authors thank their institutions that provided the economic and technical support to carry out this study.
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This work is supported by the National Council of Science and Technology of Mexico (CONACYT; Grant no. 177594).
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by RDCT, MEUG, LLMC, BED, LR, SOS, and MAV. The first draft of the manuscript was written by RDCT and MEUG and all authors commented on previous versions of the manuscript. Funding acquisition: CBZ and MEUG. All authors read and approved the final manuscript.
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Highlights
• GABA, glutamate, and VEGF signaling genes were upregulated in the temporal cortex of patients with pharmacoresistant TLE.
• G protein q polypeptide, serine racemase, and gephyrin appeared as novel genes to be studied in pharmacoresistant TLE.
• Similarly, glutamate/cystine antiporter system xCT and VEGF signaling genes should be considered for future studies in pharmacoresistant TLE.
• The VEGF signaling is confirmed as a relevant mediator in pharmacoresistant TLE.
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Castro-Torres, R.D., Ureña-Guerrero, M.E., Morales-Chacón, L.M. et al. New Aspects of VEGF, GABA, and Glutamate Signaling in the Neocortex of Human Temporal Lobe Pharmacoresistant Epilepsy Revealed by RT-qPCR Arrays. J Mol Neurosci 70, 916–929 (2020). https://doi.org/10.1007/s12031-020-01519-6
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DOI: https://doi.org/10.1007/s12031-020-01519-6