Potent inhibitors of sEH dose dependently delay onset of seizures induced by GABA antagonist.

<p>In parallel to observations with sEH−/− mice, small molecule inhibitors of sEH delay onset of tonic phase of seizure in wild type Swiss mice. In all three experiments sEHI were administered one hour prior to convulsants to allow absorption and distribution of the inhibitor. (<i>A</i>) TUPS was administered at a volume of 1 µL/g body weight by intraperitoneal route following completely dissolving it in PEG400. Subcutaneous PTZ induced tonic seizure is delayed by sEH inhibitor TUPS (n = 8–22/group, Kruskal-Wallis One Way ANOVA on Ranks followed by Dunn's multiple comparison, vehicle vs TUPS, *p = 0.028, <b>#</b> p = 0.008, <b>§</b> p = 0.03), though onset of clonic seizure was not affected by inhibition of sEH. (<i>B</i>) In parallel to results obtained by TUPS, a structurally different sEHI, TPPU delayed the onset of tonic phase of PTZ induced seizure compared to vehicle (n = 8–14/group, Kruskal-Wallis One Way ANOVA on Ranks followed by Dunn's multiple comparison, vehicle vs TPPU, **p≤0.05). Clonic phase of seizures was not monitored in this experiment. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080922#pone.0080922.s004" target="_blank">Table S1</a> for structure and potency information of TUPS and TPPU. (<i>C</i>) Seizures induced by 4-AP had a shorter onset in Swiss mice however consistent with data in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080922#pone-0080922-g001" target="_blank">Figure 1</a>, an efficacious dose of TUPS did not significantly alter onset of seizure (n = 8/group, Student's <i>t</i>-test, p = 0.49).