 <p class="lead" id="first">Researchers studying epileptic seizures of the temporal lobe -- the most common type of epilepsy -- discovered a compound that reduces seizures in the hippocampus, a brain region where many such seizures originate. The compound, known as TC-2153, lessened the severity of seizures in mice.</p><p>The scientists report their findings in the journal <em>Epilepsia.</em></p><p>"We found that TC-2153 ultimately reduces seizure severity in mice by decreasing the activity of hippocampal neurons," said University of Illinois Urbana-Champaign doctoral candidate Jennifer Walters, who led the research with U. of I. molecular and integrative physiology professor Hee Jung Chung.</p><p>"In most temporal lobe epilepsy, the seizures start in the medial temporal lobe, which includes the hippocampus," Chung said. "And 60% or more of patients who have medial temporal lobe epilepsy develop drug-resistant seizures, which correlate with the extent of neuronal death and inflammation in the hippocampus."</p><p>The hippocampus plays a central role in learning and memory, so anything that damages it can have devastating consequences for the individual, she said.</p><p>The strength of synaptic communication between neurons and the excitability of individual neurons can affect the likelihood that seizures occur, Chung said.</p><p>The finding that TC-2153 lessened the occurrence of seizures was a surprise, the researchers said, because it is known primarily as an inhibitor of a brain-specific protein called STEP that reduces the strength of synaptic communication between neurons.</p><p>"We hypothesized that seizure activity would increase when we used TC-2153 because STEP inhibition would increase synaptic communication," Walters said. "But we found that it actually reduced seizure severity in both male and female mice."</p><p>The female mice responded more to treatment with the compound than the males did. To determine whether TC-2153 interacted with sex hormones, the team repeated the experiment in female mice that had their ovaries removed.</p><p>"That completely abolished the effect from the TC-2153," Walters said. "Therefore, female sex hormones play a role in its efficacy." This finding may be relevant to sex differences seen in temporal lobe epilepsy, she said.</p><p>Follow-up experiments in mouse brains and in neuronal culture revealed a possible mechanism by which TC-2153 decreases seizure severity. The team found that the compound reduced the excitability of individual neurons, suggesting a novel function of STEP, Chung said.</p><p>"TC-2153 is a STEP inhibitor," she said. "So far, STEP has been known as a negative regulator of neuronal communication but was never implicated in regulating the excitability of individual neurons."</p><p>Further studies will explore how TC-2153 works and will test its effects in human neurons, the researchers said.</p><p>Chung is also a faculty affiliate of the Beckman Institute for Advanced Science and Technology and the Carl R. Woese Institute for Genomic Biology at Illinois.</p><p>The National Institutes of Health, University of Illinois Campus Research Board and Carle Illinois Collaborative supported this research.</p>