We have demonstrated previously that activation of either the ET_A or ET_B receptor can induce acute electrographic seizures following the intrahippocampal infusion of endothelin-1 (ET-1) in immature (P12) rats. We also demonstrated that activation of the ET_A receptor is associated with marked focal ischemia, while activation of the ET_B receptor is not.

Exploring the mechanisms underlying seizures induced by these two ET-1 receptor interactions can potentially provide insight into how focal ischemia in immature animals produces seizures and whether ischemiarelated seizures differ from seizures not associated with ischemia.

To explore these seizure mechanisms we used microdialysis to determine biomarkers associated with seizures in P12 rats following the intrahippocampal infusion of two different agents: (1) ET-1, which activates both the ET_A and ET_B receptors and causes focal ischemia and (2) Ala-ET-1, which selectively activates only the ET_B receptor and does not cause ischemia.

Our results show that seizures associated with combined ET_A and ET_B receptor activation (and ischemia) have a different temporal distribution and microdialysis profile from seizures associated with ET_B activation alone (and without ischemia). Seizures with combined activation peak within the first hour after infusion and the microdialysis profile is characterized by a significant increase in the ratio of glutamic acid to GABA. By contrast, seizures with activation of only the ET_B receptor peak in the second hour after infusion and microdialysis shows a significant increase in the ratio of leukotriene B4 to prostaglandin E2.

These findings suggest that ischemia-related seizures in immature animals involve an imbalance of excitation and inhibition, while non-ischemiarelated seizures involve an inflammatory process resulting from an excess of leukotrienes.