Abstracts

Rationale:
Epilepsy is one of the most common chronic neurological disorders affecting approximately 50 million individuals across the globe. Many new antiepileptic drugs (AEDs) have shown promise; however, current regimens fail in up to 30% of patients. There has been increasing evidence indicating a role for glial cells in the pathophysiology of epilepsy, making them a potential new target for AEDs. The cystine–glutamate exchanger (SLC7A11, xCT) is primarily expressed on astrocytes and is associated with several neurological disorders, including epilepsy. Also, xCT deletion in mice led to increased seizure threshold when compared to wild type mice.   Sulfasalazine (SAS) is an FDA approved drug for ulcerative colitis and rheumatoid arthritis.  It is also a potent inhibitor of xCT. Anti-seizure effects of SAS have been reported in the literature; however, the exact mechanism remains unknown.  A recent study suggested that the SAS may exhibit its inhibitory effects by modulating GABA uptake. To this extent, we investigated the effect of intrahippocampal SAS infusion on extracellular GABA in an animal model of epilepsy.  
Method:
To create a model of temporal lobe epilepsy (TLE), methionine sulfoximine (MSO), a glutamine synthetase enzyme inhibitor, was chronically infused in the right hippocampus of Sprague Dawley rats (n = 9). After two weeks, microdialysis probes were implanted in the right and left hippocampus of all animals. The extracellular baseline was collected for 135 mins by infusing artificial cerebral spinal fluid. Subsequently, SAS diluted in phosphate buffer (0.5 mM) was infused at 0.5 µl/min for 2 hours using the same microdialysis probes, and extracellular fluid was continuously collected.  All microdialysate samples were analyzed for GABA using mass spectrometry. All GABA values were normalized by overnight baseline GABA concentration and expressed in percent
Results:
There was no significant difference in ipsilateral and contralateral pre-treatment baseline GABA concentration. In the ipsilateral side, there was no effect of SAS on GABA. However, there was a significant increase in the GABA concentration in the contralateral side when compared to pre and post treatment baseline (p < 0.001). In addition, GABA concentration was significantly different between ipsilateral and contralateral side during the time of drug infusion (p < 0.01).
Conclusion:
Through this study, we describe the effects of SAS on extracellular hippocampal GABA. Along with xCT inhibition, an increase in GABA concentration may explain the anti-seizure effects of SAS. This drug may prove to be a potent anti-epileptic drug; however, more pre-clinical and clinical studies are warranted to test its efficacy and adverse effects.
Funding:
:NIH/NINDS