Abstract
PurposeEpilepsy therapy is currently based on anti-seizure drugs that do not modify the course of the disease, i.e., they are not anti-epileptogenic in nature. Previously, we observed that in vivo casein kinase 2 (CK2) inhibition with 4,5,6,7-tetrabromotriazole (TBB) had anti-epileptogenic effects in the acute epilepsy slice model.MethodsHere, we pretreated rats with TBB in vivo prior to the establishment of a pilocarpine-induced status epilepticus (SE) in order to analyze the long-term sequelae of such a preventive TBB administration.ResultsWe found that TBB pretreatment delayed onset of seizures after pilocarpine and slowed down disease progression during epileptogenesis. This was accompanied with a reduced proportion of burst firing neurons in the CA1 area. Western blot analyses demonstrated that CA1 tissue from TBB-pretreated epileptic animals contained significantly less CK2 than TBB-pretreated controls. On the transcriptional level, TBB pretreatment led to differential gene expression changes of KCa2.2, but also of HCN1 and HCN3 channels. Thus, in the presence of the HCN channel blocker ZD7288, pretreatment with TBB rescued the afterhyperpolarizing potential (AHP) as well as spike frequency adaptation in epileptic animals, both of which are prominent functions of KCa2 channels.ConclusionThese data indicate that TBB pretreatment prior to SE slows down disease progression during epileptogenesis involving increased KCa2 function, probably due to a persistently decreased CK2 protein expression.
Highlights
Temporal lobe epilepsy (TLE) is the most common focal symptomatic epileptic disorder in the adulthood and typically difficult to treat (Kwan and Brodie, 2000; Blümcke et al, 2013)
It appears that channels that are active near the resting membrane potential (RMP) such as K+ or hyperpolarization-activated cyclic nucleotide-gated nonselective (HCN) channels are intriguing candidates involved in epileptogenesis
We recently demonstrated that oral administration of the Casein kinase 2 (CK2) blocker 4,5,6,7-tetrabromotriazole (TBB) enhanced K+ currents mediating the afterhyperpolarizing potential (AHP) in the pilocarpine model, and even more intriguing, blocked the occurrence of spontaneous epileptic activity in the acute slice model with Mg2+ removal (Brehme et al, 2014)
Summary
Temporal lobe epilepsy (TLE) is the most common focal symptomatic epileptic disorder in the adulthood and typically difficult to treat (Kwan and Brodie, 2000; Blümcke et al, 2013). Several rodent post-status epilepticus (SE) models such as the pilocarpine animal model have provided valuable insights into the latent period between the initial insult and the subsequent development of chronic TLE (Leite et al, 2002) During this period of epileptogenesis, marked changes in synaptic and intrinsic properties take place that may facilitate the occurrence of seizures—most profoundly and studied at best—within the hippocampal network (Leite et al, 2002). With respect to the CA1 area in the pilocarpine model, there is evidence of persistent downregulation of Kv4.2 (Bernard et al, 2004), KCa2.2 (Schulz et al, 2012), and HCN1 (Jung et al, 2007, 2010) These transcriptional changes partly seem to involve the activation of protein kinases or phosphatases (Bernard et al, 2004; Jung et al, 2010). Protein kinase and/or phosphatase activation seem to be involved in acute epileptic conditions (Jung et al, 2010; Kernig et al, 2012) suggesting that neuronal hyperactivity may trigger these enzymatic pathways
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