Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis
Clinical observations and studies on different animal models of acquired epilepsy consistently demonstrate that blood–brain barrier (BBB) leakage can be an important risk factor for developing recurrent seizures. However, the involved signaling pathways remain largely unclear. Given the important ro...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-06-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996115001047 |
| _version_ | 1818651537311793152 |
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| author | D. Isaev I. Lushnikova O. Lunko O. Zapukhliak O. Maximyuk A. Romanov G.G. Skibo C. Tian G.L. Holmes E. Isaeva |
| author_facet | D. Isaev I. Lushnikova O. Lunko O. Zapukhliak O. Maximyuk A. Romanov G.G. Skibo C. Tian G.L. Holmes E. Isaeva |
| author_sort | D. Isaev |
| collection | DOAJ |
| description | Clinical observations and studies on different animal models of acquired epilepsy consistently demonstrate that blood–brain barrier (BBB) leakage can be an important risk factor for developing recurrent seizures. However, the involved signaling pathways remain largely unclear. Given the important role of thrombin and its major receptor in the brain, protease-activated receptor 1 (PAR1), in the pathophysiology of neurological injury, we hypothesized that PAR1 may contribute to status epilepticus (SE)-induced epileptogenesis and that its inhibition shortly after SE will have neuroprotective and antiepileptogenic effects. Adult rats subjected to lithium–pilocarpine SE were administrated with SCH79797 (a PAR1 selective antagonist) after SE termination. Thrombin and PAR1 levels and neuronal cell survival were evaluated 48 h following SE. The effect of PAR1 inhibition on animal survival, interictal spikes (IIS) and electrographic seizures during the first two weeks after SE and behavioral seizures during the chronic period was evaluated. SE resulted in a high mortality rate and incidence of IIS and seizures in the surviving animals. There was a marked increase in thrombin, decrease in PAR1 immunoreactivity and hippocampal cell loss in the SE-treated rats. Inhibition of PAR1 following SE resulted in a decrease in mortality and morbidity, increase in neuronal cell survival in the hippocampus and suppression of IIS, electrographic and behavioral seizures following SE.These data suggest that the PAR1 signaling pathway contributes to epileptogenesis following SE. Because breakdown of the BBB occurs frequently in brain injuries, PAR1 inhibition may have beneficial effects in a variety of acquired injuries leading to epilepsy. |
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| format | Article |
| id | doaj.art-9c82b14a09f14b1fb134819c5454c471 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T02:07:41Z |
| publishDate | 2015-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-9c82b14a09f14b1fb134819c5454c4712022-12-21T22:07:38ZengElsevierNeurobiology of Disease1095-953X2015-06-01786876Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesisD. Isaev0I. Lushnikova1O. Lunko2O. Zapukhliak3O. Maximyuk4A. Romanov5G.G. Skibo6C. Tian7G.L. Holmes8E. Isaeva9Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USADepartment of Cytology, Bogomoletz Institute of Physiology, Kiev, UkraineDepartment of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, UkraineDepartment of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, UkraineDepartment of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, UkraineDepartment of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, UkraineDepartment of Cytology, Bogomoletz Institute of Physiology, Kiev, UkraineDepartment of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USADepartment of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USADepartment of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA; Corresponding author at: Department of Cellular Membranology, Bogomoletz Institute of Physiology, 4 Bogomoletz Str, Kiev 01024, Ukraine. Fax: +380 442562000.Clinical observations and studies on different animal models of acquired epilepsy consistently demonstrate that blood–brain barrier (BBB) leakage can be an important risk factor for developing recurrent seizures. However, the involved signaling pathways remain largely unclear. Given the important role of thrombin and its major receptor in the brain, protease-activated receptor 1 (PAR1), in the pathophysiology of neurological injury, we hypothesized that PAR1 may contribute to status epilepticus (SE)-induced epileptogenesis and that its inhibition shortly after SE will have neuroprotective and antiepileptogenic effects. Adult rats subjected to lithium–pilocarpine SE were administrated with SCH79797 (a PAR1 selective antagonist) after SE termination. Thrombin and PAR1 levels and neuronal cell survival were evaluated 48 h following SE. The effect of PAR1 inhibition on animal survival, interictal spikes (IIS) and electrographic seizures during the first two weeks after SE and behavioral seizures during the chronic period was evaluated. SE resulted in a high mortality rate and incidence of IIS and seizures in the surviving animals. There was a marked increase in thrombin, decrease in PAR1 immunoreactivity and hippocampal cell loss in the SE-treated rats. Inhibition of PAR1 following SE resulted in a decrease in mortality and morbidity, increase in neuronal cell survival in the hippocampus and suppression of IIS, electrographic and behavioral seizures following SE.These data suggest that the PAR1 signaling pathway contributes to epileptogenesis following SE. Because breakdown of the BBB occurs frequently in brain injuries, PAR1 inhibition may have beneficial effects in a variety of acquired injuries leading to epilepsy.http://www.sciencedirect.com/science/article/pii/S0969996115001047ThrombinProtease-activated receptorHippocampusPilocarpineEpileptogenesisStatus epilepticus |
| spellingShingle | D. Isaev I. Lushnikova O. Lunko O. Zapukhliak O. Maximyuk A. Romanov G.G. Skibo C. Tian G.L. Holmes E. Isaeva Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis Neurobiology of Disease Thrombin Protease-activated receptor Hippocampus Pilocarpine Epileptogenesis Status epilepticus |
| title | Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis |
| title_full | Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis |
| title_fullStr | Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis |
| title_full_unstemmed | Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis |
| title_short | Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis |
| title_sort | contribution of protease activated receptor 1 in status epilepticus induced epileptogenesis |
| topic | Thrombin Protease-activated receptor Hippocampus Pilocarpine Epileptogenesis Status epilepticus |
| url | http://www.sciencedirect.com/science/article/pii/S0969996115001047 |
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