Holtkamp, Dominik: Mechanisms of action of novel antiepileptic drugs in chronic epileptic hippocampus. - Bonn, 2019. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-54714
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-54714,
author = {{Dominik Holtkamp}},
title = {Mechanisms of action of novel antiepileptic drugs in chronic epileptic hippocampus},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2019,
month = may,

note = {Globally, at least 50 million people suffer from epilepsy and almost one third of these do not respond to treatment with one or even multiple antiepileptic drugs (AEDs). One of the most prominent approaches trying to explain this phenomenon termed pharmacoresistance is the target-hypothesis. It implies that epilepsy-related or seizure-induced alterations in the properties of the molecular targets of AEDs occur and ultimately result in reduced drug sensitivity.
Voltage-gated sodium channels constitute one of the key targets for many AEDs (so-called sodium channel blockers), as they are crucial for neuronal excitation and for signal transduction in the brain. For the anticonvulsant carbamazepine but also other older sodium channel blockers a strong reduction of efficacy in use-dependent blocking of sodium channels and thereby reduction of repetitive neuronal firing was shown in epileptic tissue of animal models of epilepsy as well as epilepsy patients. While older sodium channel blockers including carbamazepine interfere with the fast inactivation of sodium channels, the novel AEDs lacosamide and eslicarbazepine acetate (via its active metabolite eslicarbazepine) were shown to modulate slow inactivation of sodium channels, in contrast. Due to this unique mechanism of action both compounds were proposed to be candidate drugs to overcome pharmacoresistance.
Using the patch-clamp technique, this thesis aimed at investigating the mechanism of action and the efficacy of both substances on granule cells of the dentate gyrus, which plays an important role in limiting the spread of epileptic seizures and thereby preventing temporal lobe seizures from generalizing. Since previous studies were mostly performed on physiologically different cultured cell lines, here, multiple aspects of the still not completely understood slow inactivation of sodium channels in dentate granule cells were in the focus of investigations. Furthermore, in order to identify potential reductions in efficacy or changes in the mechanism of action of lacosamide and eslicarbazepine, comparisons between healthy and epileptic tissue were made using the pilocarpine model of epilepsy. Identical experiments were also conducted in human epileptic brain tissue that was provided after surgical removal of the epileptic foci of treatment resistant epilepsy patients. We could show that both substances exert potent efficacy on the slow sodium channel inactivation, particularly on the voltage dependence of slow inactivation (implied by a strong hyperpolarizing shift of the inactivation curve) also in dentate granule cells. Much less pronounced effects on sodium channel fast inactivation processes were demonstrated for eslicarbazepine in an earlier study and for lacosamide within this thesis. These effects appear to be negligible when compared to the prominent shifts of the voltage dependence of slow inactivation, however. Interestingly, all of the reported effects were not limited to healthy dentate granule cells but could also be replicated in rat and human epileptic granule cells in unaltered magnitude.
As described for lacosamide within this work and for eslicarbazepine in an earlier study, the observed effects on the slow inactivation of sodium channels translate into inhibition of action potential firing of dentate granule cells in response to prolonged depolarization – again without differences between epileptic and nonepileptic cells. Subsequent analyses of the action potential firing behavior during application of lacosamide revealed that the effects on slow inactivation processes translate into systematic changes in the action potential waveform that further increase with the duration of depolarization.
To sum up, lacosamide as well as eslicarbazepine show relatively small effects on fast inactivation processes while strongly modulating the slow inactivation of sodium channels and its voltage dependence. This is reflected by a reduction of the granule cell firing behavior. For all of the effects described, no differences between granule cells of epileptic and nonepileptic origin were observed. On the basis of these results it can be concluded that both of the investigated substances have the potential to overcome the resistance mechanism described for carbamazepine and other sodium channel blockers, at least in the light of the target-hypothesis.},

url = {http://hdl.handle.net/20.500.11811/7930}

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