We have demonstrated previously that activation of either the ETA or ETB 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 ETA receptor is associated with marked focal ischemia, while activation of the ETB 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 ETA and ETB receptors and causes focal ischemia and (2) Ala-ET-1, which selectively activates only the ETB receptor and does not cause ischemia. Our results show that seizures associated with combined ETA and ETB receptor activation (and ischemia) have a different temporal distribution and microdialysis profile from seizures associated with ETB 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 ETB 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.

Department of Developmental Epileptology Institute of Physiology of the Czech Academy of Sciences Videnska 1083 14220 Prague Czech Republic

Department of Neurosciences Biomedicine and Movement Sciences University of Verona Strada le Grazie 8 37134 Verona Italy

Essence Line Plzeňská 130 221 150 00 Prague 5 Czech Republic

Faculty of Science Charles university Prague Albertov 6 12843 Prague Czech Republic

INN Istituto Nazionale delle Neuroscienze Verona Italy

National Institute of Mental Health Topolova 748 25067 Klecany Czech Republic

Strong Epilepsy Center Department of Neurology University of Rochester Medical Center 601 Elmwood Avenue Box 673 Rochester NY 14642 USA

Veterinary Clinic Well vet 14100 Prague Czech Republic

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$a Vondrakova, Katerina $u Department of Developmental Epileptology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic; Faculty of Science, Charles university in Prague, Albertov 6, 12843 Prague, Czech Republic; National Institute of Mental Health, Topolova 748, 25067 Klecany, Czech Republic.

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$a Electrographic seizures induced by activation of ETA and ETB receptors following intrahippocampal infusion of endothelin-1 in immature rats occur by different mechanisms / $c K. Vondrakova, P. Novotny, H. Kubova, A. Posusta, J. Boron, V. Faberova, PF. Fabene, J. Burchfiel, G. Tsenov,

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$a We have demonstrated previously that activation of either the ETA or ETB 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 ETA receptor is associated with marked focal ischemia, while activation of the ETB 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 ETA and ETB receptors and causes focal ischemia and (2) Ala-ET-1, which selectively activates only the ETB receptor and does not cause ischemia. Our results show that seizures associated with combined ETA and ETB receptor activation (and ischemia) have a different temporal distribution and microdialysis profile from seizures associated with ETB 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 ETB 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.

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$a Novotny, Petr $u Essence Line, Plzeňská 130/221, 150 00 Prague 5, Czech Republic.

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$a Kubova, Hana $u Department of Developmental Epileptology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic.

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$a Posusta, Antonin $u Department of Developmental Epileptology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic.

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$a Faberova, Veronika $u Department of Developmental Epileptology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic; Veterinary Clinic Well-vet, 14100 Prague, Czech Republic.

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$a Fabene, Paolo Francesco $u Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada le Grazie 8, 37134 Verona, Italy; INN, Istituto Nazionale delle Neuroscienze, Verona, Italy.

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$a Burchfiel, James $u Strong Epilepsy Center, Department of Neurology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 673, Rochester, NY 14642, USA.

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$a Tsenov, Grygoriy $u Department of Developmental Epileptology, Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic; National Institute of Mental Health, Topolova 748, 25067 Klecany, Czech Republic; Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada le Grazie 8, 37134 Verona, Italy. Electronic address: grygoriy.tsenov@gmail.com.

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