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Title: Studies of biomarkers in temporal lobe epilepsy
Author: Sheilabi, Marim Abdelghani
ISNI:       0000 0004 6351 2951
Awarding Body: Sheffield Hallam University
Current Institution: Sheffield Hallam University
Date of Award: 2016
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Purpose: Refractory temporal lobe epilepsy associated with hippocampal sclerosis (TLE-HS) affects about 30% of TLE patients, where antiepileptic drugs are not effective in controlling seizures. These patients become candidates for surgical treatment which is effective in only 60-70% of cases. In addition, surgical treatment causes memory and cognitive impairments as well as psychopathological disturbance. Therefore, the aim of this study is to investigate potential biomarkers in surgically resected sclerotic TLE-HS (n = 49) and non-spiking superior temporal gyrus samples (TLE-STG; n = 25) from TLE patients and post-mortem hippocampi (PMC; n = 10), in order to increase our understanding of refractory TLE pathophysiology and help in identifying new potential drug targets for treatment of TLE patients. Methods: GABAb receptor subunits were investigated in TLE-HS, TLE-STG and PMC tissue by quantitative real time polymerase chain reaction (qRT-PCR) and quantitative western blot (WB) techniques. Alterations in expressions of SGK1, SCN4B, IP3R1 and SYNPR were investigated in TLE-HS, TLE-STG and PMC specimens by qRT-PCR and WB. The transcriptome profiling of TLE-HS, TLE- STG and PMC samples was done by microarray analysis (MA). MA was followed by functional annotation clustering analysis (FAC) of the MA differentially expressed genes (DEGs). Genes from FAC analysis were further investigated by qRT-PCR. MA Aquaporin (AQP1, 3, 4, 5, 8, 9, 11) expressions were further validated by qRT-PCR. Results: Expression of the inhibitory GABAB2 receptor subunit was significantly up regulated in TLE-HS compared to PMC but its expression was reduced in TLE-HS compared to TLE-STG.The expression of SCN4B, IP3R1 and SYNPR, which are involved in regulating neuronal excitability, were significantly reduced in TLE-HS compared to TLE-STG and were significantly increased compared to PMC. The expression of SGK1 mRNA was significantly increased in TLE-HS compared to both TLE-STG and PMC. MA analysis revealed 1821 genes were significantly up regulated and 1511 genes were significantly down regulated in TLE-HS compared to TLE-STG and PMC. The first cluster from FAC analysis of DEGs showed that the up regulated inflammatory genes such as cytokines had the highest enrichment score. The qRT-PCR data showed that expression of IL-13, IL-18, Fas, ICAM-1, CCL2, CCL4, CXCL1, CXCL2, CXCL12, CXCR4 and CX3CR1 were significantly higher in TLE-HS compared to TLE-STG and PMC therefore validating MA data. AQP1 and -4, which are involved in water homeostasis, were significantly up regulated in TLE-HS compared to TLE-STG. AQP11 expression was significantly reduced in TLE-HS while AQP3, -5, -8 and -9 were not significantly altered in TLE-HS compared to TLE-STG and PMC. Discussion: The significant dysregulation of biomarker expression investigated in this study indicate that different biological processes such as neuronal excitability, neuronal and astrocytic energy metabolism, neurogenesis, apoptosis, neuroinflammation, intracellular calcium and water homeostasis are affected in the epileptogenic TLE-HS tissue. These biomarkers seem to be associated with TLE-HS pathophysiology. Furthermore, they highlight the role of neuronal, astrocytic, microglia and endothelial cell dysfunction in TLE-HS pathology. In conclusion, the biomarkers investigated increased our understanding of biological processes affected in TLE-HS pathophysiology and they represent potential drug targets for refractory TLE-HS. However, further research is still needed to understand the temporal and spatial changes of those genes and their proteins during TLE.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available