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Thrombin facilitates seizures through activation of persistent sodium current.

ABSTRACT: 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.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.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.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.

SUBMITTER: Isaeva E

PROVIDER: S-EPMC3430976 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other

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Thrombin facilitates seizures through activation of persistent sodium current.

Isaeva Elena E Hernan Amanda A Isaev Dmytro D Holmes Gregory L GL

Annals of neurology 20120801 2

<h4>Objective</h4>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 ...[more]

PMID: 22926852

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Project description:Objective:Ion channels belonging to subfamily A of voltage-gated potassium channels (Kv1) are highly expressed on axons, where they play a key role in determining resting membrane potential, in shaping action potentials, and in modulating action potential frequency during repetitive neuronal firing. We aimed to study the genesis of seizures caused by mutations affecting Kv1 channels and searched for potential therapeutic targets. Methods:We used a novel in silico model, the laminar cortex model (LCM), to examine changes in neuronal excitability and network dynamics associated with loss-of-function mutations in Kv1 channels. The LCM simulates the activities of a network of tens of thousands of interconnected neurons and incorporates the kinetics of 11 types of ion channel and three classes of neurotransmitter receptor. Changes in two types of potassium currents conducted by Kv1 channels were examined: slowly inactivating D-type currents and rapidly inactivating A-type currents. Effects on neuronal firing rate, action potential shape, and neuronal oscillation state were evaluated. A systematic parameter scan was performed to identify parameter changes that can reverse the effects of the changes. Results:Reduced axonal D-type currents led to lower firing threshold and widened action potentials, both lowering the seizure threshold. Two potential therapeutic targets for treating seizures caused by loss-of-function changes in Kv1 channels were identified: persistent sodium channels and NMDA receptors. Blocking persistent sodium channels restored the firing threshold and reduced action potential width. NMDA receptor antagonists reduced excitatory postsynaptic currents from excessive glutamate release related to widened action potentials. Significance:Riluzole reduces persistent sodium currents and excitatory postsynaptic currents from NMDA receptor activation. Our results suggest that this FDA-approved drug can be repurposed to treat epilepsies caused by mutations affecting axonal Kv1 channels.

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Thrombin facilitates seizures through activation of persistent sodium current.

Publications

Thrombin facilitates seizures through activation of persistent sodium current.

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