Prevention of Epilepsy: Issues and Innovations

Schmidt, Dieter; Sillanpää, Matti

doi:10.1007/s11910-016-0695-9

Cited by 21 publications

(6 citation statements)

References 18 publications

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“…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). Moreover, all currently available drugs used to treat focal symptomatic epilepsy are merely anti-seizure drugs, i.e., they are anti-ictogenic in nature, but lack any anti-epileptogenic potential (Schmidt and Sillanpää, 2016). In the last decades, 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).…”

Section: Introductionmentioning

confidence: 99%

CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease Progression

Schulze

Müller

Guli

et al. 2020

Front. Cell. Neurosci.

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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 K Ca 2.2, 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 K Ca 2 channels. Conclusion: These data indicate that TBB pretreatment prior to SE slows down disease progression during epileptogenesis involving increased K Ca 2 function, probably due to a persistently decreased CK2 protein expression.

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Section: Introductionmentioning

confidence: 99%

CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease Progression

Schulze

Müller

Guli

et al. 2020

Front. Cell. Neurosci.

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“…Different kinds of cerebral injury, such as head trauma, stroke, cerebral infection, and status epilepticus (SE), may lead to the development of epilepsy in a certain proportion of affected patients ( Pitkänen and Immonen, 2014 ; Schmidt and Sillanpää, 2016 ). The mechanisms subjacent to the process of epileptogenesis following brain insults, though, are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Blood–Brain Barrier Leakage during Early Epileptogenesis Is Associated with Rapid Remodeling of the Neurovascular Unit

Bankstahl

Breuer

Leiter

et al. 2018

eNeuro

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Increased permeability of the blood–brain barrier (BBB) following cerebral injury results in regional extravasation of plasma proteins and can critically contribute to the pathogenesis of epilepsy. Here, we comprehensively explore the spatiotemporal evolution of a main extravasation component, albumin, and illuminate associated responses of the neurovascular unit (NVU) contributing to early epileptogenic neuropathology. We applied translational in vivo MR imaging and complementary immunohistochemical analyses in the widely used rat pilocarpine post–status epilepticus (SE) model. The observed rapid BBB leakage affected major epileptogenesis-associated brain regions, peaked between 1 and 2 d post-SE, and rapidly declined thereafter, accompanied by cerebral edema generally following the same time course. At peak of BBB leakage, serum albumin colocalized with NVU constituents, such as vascular components, neurons, and brain immune cells. Surprisingly, astroglial markers did not colocalize with albumin, and aquaporin-4 (AQP4) was clearly reduced in areas of leaky BBB, indicating a severe disturbance of astrocyte-mediated endothelial-neuronal coupling. In addition, a distinct adaptive reorganization process of the NVU vasculature apparently takes place at sites of albumin presence, substantiated by reduced immunoreactivity of endothelial and changes in vascular basement membrane markers. Taken together, degenerative events at the level of the NVU, affecting vessels, astrocytes, and neurons, seem to outweigh reconstructive processes. Considering the rapidly occurring BBB leakage and subsequent impairment of the NVU, our data support the necessity of a prompt BBB-restoring treatment as one component of rational therapeutic intervention to prevent epileptogenesis and the development of other detrimental sequelae of SE.

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“…Acquired epilepsies that develop after brain insults such as trauma are particularly refractory to treatments yet are potentially preventable if the underlying mechanisms are identified and appropriately targeted . A wealth of preclinical and clinical studies predict that neuronal excitability and plasticity act alongside inflammatory processes and contribute to epileptogenesis .…”

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confidence: 99%

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

Korgaonkar

Liu

Sekhar

et al. 2020

Annals of Neurology

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Objective Traumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll‐like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury. Methods Slice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury. Results The studies identify that TLR4 signaling in neurons augments dentate granule cell calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (CP‐AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. Interpretation These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post‐traumatic neuronal excitability. Moreover, the TLR4‐dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4‐mediated increase in CP‐AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497–515

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Prevention of Epilepsy: Issues and Innovations

Cited by 21 publications

References 18 publications

CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease Progression

CK2 Inhibition Prior to Status Epilepticus Persistently Enhances KCa2 Function in CA1 Which Slows Down Disease Progression

Blood–Brain Barrier Leakage during Early Epileptogenesis Is Associated with Rapid Remodeling of the Neurovascular Unit

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

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