Abstracts

Rationale: Adenosine (an endogenous anticonvulsant) pathway in drug resistant epilepsy (DRE) due to hippocampal sclerosis (HS) is largely unexplored. Here, we employed a pathway driven analysis strategy to probe into expression levels of genes involved in adenosine pathway and correlate findings with clinical phenotypes of DRE-HS patients. Methods: We used quantitative polymerase chain reaction, western blotting and immunohistochemistry techniques to analyze ten genes involved in adenosine pathway: ADARB1, ADK, NT5E, ADORA1, C-FOS, C-MYC, CREB1, C-JUN, NF-kB1 and MAPK1, in surgically resected sclerosed hippocampi (n=37) and compared their expressions with control hippocampi (n=38) obtained from autopsy. Expression analyses were also carried out in peripheral blood (n=21) of the same patients and results were compared with blood from healthy controls (n=30). Gene expression analysis was also performed in pre- and post surgery blood samples of the same patients from blood samples cohort (n=6). Further, genotype-phenotype correlations were done based on clinical and molecular genetic analysis.  Results: There was a consistent up-regulation of genes in adenosine pathway in hippocampi. Some genes viz. NT5E, C-MYC, MAPK1 and CREB1 were up-regulated both in hippocampi and peripheral blood in same patients. Gene expression analysis on peripheral blood following surgery showed reversal of expressions of ADARB1, NF-kB1, MAPK1 and CREB1. Analysis of genes in the pathway suggests that up-regulation of ADK, ADARB1, C-FOS, C-MYC and C-JUN may predispose patients to seizures. Significant genotype-phenotype correlations were observed: ADK up-regulation with psychogenic non-epileptic seizures (p=0.05), ADORA1 up-regulation with epileptiform discharges in ipsilateral temporal cortex (p=0.05) and C-FOS and C-MYC up-regulation with neuronal loss in hippocampus (p=0.009 & 0.05 respectively). Conclusions: Genes with similar expression pattern in brain and peripheral blood have the potential to be used as blood biomarkers for DRE. Reversal of gene expression in post-surgery blood suggests seizure sensitivity to surgery. Genotype-phenotype correlations highlight several novel observations of patho-genetic and therapeutic importance. Funding: None