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  • Title: Thrombin facilitates seizures through activation of persistent sodium current.
    Author: Isaeva E, Hernan A, Isaev D, Holmes GL.
    Journal: Ann Neurol; 2012 Aug; 72(2):192-8. PubMed ID: 22926852.
    Abstract:
    OBJECTIVE: An epileptic seizure is frequently the presenting sign of intracerebral hemorrhage (ICH) caused by stroke, head trauma, hypertension, and a wide spectrum of disorders. However, the cellular mechanisms responsible for occurrence of seizures during ICH have not been established. During intracerebral bleeding, blood constituents enter the neuronal tissue and produce both an acute and a delayed effect on brain functioning. Among the blood components, only thrombin has been shown to evoke seizures immediately after entering brain tissue. In the present study, we tested the hypothesis that thrombin increases neuronal excitability in the immature brain through alteration of voltage-gated sodium channels. METHODS: The thrombin effect on neuronal excitability and voltage-gated sodium channels was assessed using extracellular and intracellular recording techniques in the hippocampal slice preparation of immature rats. RESULTS: We show that thrombin increased neuronal excitability in the immature hippocampus in an N-methyl-D-aspartate-independent manner. Application of thrombin did not alter transient voltage-gated sodium channels and action potential threshold. However, thrombin significantly depolarized the membrane potential and produced a hyperpolarizing shift of tetrodotoxin-sensitive persistent voltage-gated sodium channel activation. This effect of thrombin was attenuated by application of protease-activated receptor-1 and protein kinase C antagonists. INTERPRETATION: Our data indicate that thrombin amplifies the persistent voltage-gated sodium current affecting resting membrane potential and seizure threshold at the network level. Our results provide a novel explanation as to how ICH in newborns results in seizures, which may provide avenues for therapeutic intervention in the prevention of post-ICH seizures.
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