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Published on: January 29, 2018
CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease
Felix Schulze1, Steffen Müller1, Xiati Guli1
1Oscar Langendorff Institute of Physiology, University of Rostock, Rostock, Germany.
Purpose:
Epilepsy 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.
Methods:
Here, 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.
Results:
We 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.
Conclusion:
These 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.
Insights
Preventive treatment with casein kinase 2 (CK2) inhibitor TBB slowed epilepsy progression in rats. This involved reduced CK2 expression and enhanced KCa2 channel function, suggesting a novel anti-epileptogenic strategy.
Area of Science:
- Neuroscience
- Pharmacology
- Epileptology
Background:
- Current epilepsy therapies primarily manage seizures but do not halt disease progression.
- Anti-epileptogenic treatments are needed to modify the underlying disease course.
- Previous studies showed casein kinase 2 (CK2) inhibition by TBB has anti-epileptogenic effects in acute epilepsy models.
Purpose of the Study:
- To investigate the long-term effects of *in vivo* TBB pretreatment before inducing status epilepticus (SE) in rats.
- To determine if preventive TBB administration impacts epileptogenesis and its molecular underpinnings.
Main Methods:
- Rats were pretreated with TBB *in vivo* before pilocarpine-induced SE.
- Long-term sequelae of TBB administration were analyzed.
- Neuronal activity, CK2 protein levels, and gene expression (KCa2.2, HCN1, HCN3) were assessed.
Main Results:
- TBB pretreatment delayed seizure onset and slowed disease progression during epileptogenesis.
- A reduced proportion of burst firing neurons was observed in the CA1 area.
- TBB-treated epileptic rats showed decreased CA1 CK2 protein levels and altered gene expression of KCa2.2, HCN1, and HCN3 channels.
- TBB pretreatment rescued afterhyperpolarizing potential (AHP) and spike frequency adaptation in epileptic rats, indicating enhanced KCa2 channel function.
Conclusions:
- Preventive TBB administration prior to SE slows epileptogenesis.
- This effect is associated with increased KCa2 channel function, likely due to persistently decreased CK2 protein expression.
- TBB shows potential as an anti-epileptogenic agent.
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