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Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis. Neurobiol Dis 2015 Jun;78:68-76

Date

04/07/2015

Pubmed ID

25843668

Pubmed Central ID

PMC4682556

DOI

10.1016/j.nbd.2015.03.026

Scopus ID

2-s2.0-84926617762   15 Citations

Abstract

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 48h 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.

Author List

Isaev D, Lushnikova I, Lunko O, Zapukhliak O, Maximyuk O, Romanov A, Skibo GG, Tian C, Holmes GL, Isaeva E

Author

Olena Isaeva PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Body Weight
CA1 Region, Hippocampal
Male
Pyrroles
Quinazolines
Rats
Rats, Wistar
Receptor, PAR-1
Status Epilepticus
Thrombin