Preservation of Astrocytic Coupling Prevents Epileptogenesis
Preservation of Astrocytic Coupling Prevents Epileptogenesis
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DissertationDate of Exam
14.09.2018Date of Publication
23.10.2018Advisor
Steinhäuser, ChristianCo-Referee
Müller, Christa E.Metadata
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Abstract
Antiepileptic therapies are mainly based on drugs which target neuronal function. One third of epileptic patients do not respond adequately to these treatments and, importantly, all available drugs merely suppress seizures without curing the underlying disorder. Consequentially, new strategies for the development of antiepileptogenic drugs are urgently needed.
Brain inflammation contributes to a loss of gap junction-mediated coupling between astrocytes, which is a causal event in the development of temporal lobe epilepsy (TLE). In a first step we assessed the effect of XPro1595 (a selective inhibitor of soluble TNF- alpha) and Anakinra (IL-1R antagonist) in situ in acute brain slices from epileptic mice and found that astrocytic coupling was restored. To investigate this in more detail, we checked the cytokine levels in the intracortical kainate (KA) model using ELISA. The results show elevated TNF-alpha levels immediately after KA-induced status epilepticus (SE), whereas IL-1beta was less prominent. This finding prompted us to assess the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling. Hence, we investigated the effect of XPro1595 i.p. injection on astrocytic coupling and the development of TLE. The results show that XPro1595 given in vivo prior to KA injection prevented the loss of astrocytic gap junction coupling and thus the development of generalised spontaneous seizures and hippocampal sclerosis (HS) were prevented.
Treatment with XPro1595 in vivo after KA injection rescued astrocytic coupling, significantly decreased chronic seizure frequency in the long-term and attenuated HS-specific morphological alterations.
To confirm the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling, we used transgenic TNFR1 KO animals in our epilepsy model. We could show that TNFR1 KO astrocytic coupling was unaltered after SE-induction, indicating that TNFR1 activation regulates astrocytic coupling strength. Furthermore, these animals showed significantly less seizure activity, demonstrating the importance of astrocytic coupling on the progression of TLE. However, incubation of acute brain slices from wildtype mice with TNF-alpha in situ revealed no impaired astrocytic coupling. Therefore, we suggest that a second mediator, like IL-1beta or a yet unknown molecule, might be needed to induce astrocytic uncoupling.
In conclusion, this study demonstrates that solTNF-alpha/TNFR1 mediates astrocytic uncoupling and plays a key role in the development of TLE-HS. Rescuing astrocytic coupling might represent a new strategy to develop antiepileptogenic therapies. The present project elucidated the therapeutic potential of targeting astrocytic proteins in epilepsy and also shed further light on the mechanisms underlying the disorder.
Brain inflammation contributes to a loss of gap junction-mediated coupling between astrocytes, which is a causal event in the development of temporal lobe epilepsy (TLE). In a first step we assessed the effect of XPro1595 (a selective inhibitor of soluble TNF- alpha) and Anakinra (IL-1R antagonist) in situ in acute brain slices from epileptic mice and found that astrocytic coupling was restored. To investigate this in more detail, we checked the cytokine levels in the intracortical kainate (KA) model using ELISA. The results show elevated TNF-alpha levels immediately after KA-induced status epilepticus (SE), whereas IL-1beta was less prominent. This finding prompted us to assess the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling. Hence, we investigated the effect of XPro1595 i.p. injection on astrocytic coupling and the development of TLE. The results show that XPro1595 given in vivo prior to KA injection prevented the loss of astrocytic gap junction coupling and thus the development of generalised spontaneous seizures and hippocampal sclerosis (HS) were prevented.
Treatment with XPro1595 in vivo after KA injection rescued astrocytic coupling, significantly decreased chronic seizure frequency in the long-term and attenuated HS-specific morphological alterations.
To confirm the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling, we used transgenic TNFR1 KO animals in our epilepsy model. We could show that TNFR1 KO astrocytic coupling was unaltered after SE-induction, indicating that TNFR1 activation regulates astrocytic coupling strength. Furthermore, these animals showed significantly less seizure activity, demonstrating the importance of astrocytic coupling on the progression of TLE. However, incubation of acute brain slices from wildtype mice with TNF-alpha in situ revealed no impaired astrocytic coupling. Therefore, we suggest that a second mediator, like IL-1beta or a yet unknown molecule, might be needed to induce astrocytic uncoupling.
In conclusion, this study demonstrates that solTNF-alpha/TNFR1 mediates astrocytic uncoupling and plays a key role in the development of TLE-HS. Rescuing astrocytic coupling might represent a new strategy to develop antiepileptogenic therapies. The present project elucidated the therapeutic potential of targeting astrocytic proteins in epilepsy and also shed further light on the mechanisms underlying the disorder.
Subjects
TNFalpha, temporal lobe epilepsy, astrocyte, glia, gap junction coupling, sclerosis, antiepileptic drug, inflammation
Classification (DDC)
570 Biowissenschaften, BiologieMüller, Julia: Preservation of Astrocytic Coupling Prevents Epileptogenesis. - Bonn, 2018. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-52153
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-52153
@phdthesis{handle:20.500.11811/7647,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-52153,
author = {{Julia Müller}},
title = {Preservation of Astrocytic Coupling Prevents Epileptogenesis},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2018,
month = oct,
note = {Antiepileptic therapies are mainly based on drugs which target neuronal function. One third of epileptic patients do not respond adequately to these treatments and, importantly, all available drugs merely suppress seizures without curing the underlying disorder. Consequentially, new strategies for the development of antiepileptogenic drugs are urgently needed.
Brain inflammation contributes to a loss of gap junction-mediated coupling between astrocytes, which is a causal event in the development of temporal lobe epilepsy (TLE). In a first step we assessed the effect of XPro1595 (a selective inhibitor of soluble TNF- alpha) and Anakinra (IL-1R antagonist) in situ in acute brain slices from epileptic mice and found that astrocytic coupling was restored. To investigate this in more detail, we checked the cytokine levels in the intracortical kainate (KA) model using ELISA. The results show elevated TNF-alpha levels immediately after KA-induced status epilepticus (SE), whereas IL-1beta was less prominent. This finding prompted us to assess the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling. Hence, we investigated the effect of XPro1595 i.p. injection on astrocytic coupling and the development of TLE. The results show that XPro1595 given in vivo prior to KA injection prevented the loss of astrocytic gap junction coupling and thus the development of generalised spontaneous seizures and hippocampal sclerosis (HS) were prevented.
Treatment with XPro1595 in vivo after KA injection rescued astrocytic coupling, significantly decreased chronic seizure frequency in the long-term and attenuated HS-specific morphological alterations.
To confirm the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling, we used transgenic TNFR1 KO animals in our epilepsy model. We could show that TNFR1 KO astrocytic coupling was unaltered after SE-induction, indicating that TNFR1 activation regulates astrocytic coupling strength. Furthermore, these animals showed significantly less seizure activity, demonstrating the importance of astrocytic coupling on the progression of TLE. However, incubation of acute brain slices from wildtype mice with TNF-alpha in situ revealed no impaired astrocytic coupling. Therefore, we suggest that a second mediator, like IL-1beta or a yet unknown molecule, might be needed to induce astrocytic uncoupling.
In conclusion, this study demonstrates that solTNF-alpha/TNFR1 mediates astrocytic uncoupling and plays a key role in the development of TLE-HS. Rescuing astrocytic coupling might represent a new strategy to develop antiepileptogenic therapies. The present project elucidated the therapeutic potential of targeting astrocytic proteins in epilepsy and also shed further light on the mechanisms underlying the disorder.},
url = {https://hdl.handle.net/20.500.11811/7647}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-52153,
author = {{Julia Müller}},
title = {Preservation of Astrocytic Coupling Prevents Epileptogenesis},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2018,
month = oct,
note = {Antiepileptic therapies are mainly based on drugs which target neuronal function. One third of epileptic patients do not respond adequately to these treatments and, importantly, all available drugs merely suppress seizures without curing the underlying disorder. Consequentially, new strategies for the development of antiepileptogenic drugs are urgently needed.
Brain inflammation contributes to a loss of gap junction-mediated coupling between astrocytes, which is a causal event in the development of temporal lobe epilepsy (TLE). In a first step we assessed the effect of XPro1595 (a selective inhibitor of soluble TNF- alpha) and Anakinra (IL-1R antagonist) in situ in acute brain slices from epileptic mice and found that astrocytic coupling was restored. To investigate this in more detail, we checked the cytokine levels in the intracortical kainate (KA) model using ELISA. The results show elevated TNF-alpha levels immediately after KA-induced status epilepticus (SE), whereas IL-1beta was less prominent. This finding prompted us to assess the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling. Hence, we investigated the effect of XPro1595 i.p. injection on astrocytic coupling and the development of TLE. The results show that XPro1595 given in vivo prior to KA injection prevented the loss of astrocytic gap junction coupling and thus the development of generalised spontaneous seizures and hippocampal sclerosis (HS) were prevented.
Treatment with XPro1595 in vivo after KA injection rescued astrocytic coupling, significantly decreased chronic seizure frequency in the long-term and attenuated HS-specific morphological alterations.
To confirm the effect of solTNF-alpha/TNFR1 signalling cascade on astrocytic coupling, we used transgenic TNFR1 KO animals in our epilepsy model. We could show that TNFR1 KO astrocytic coupling was unaltered after SE-induction, indicating that TNFR1 activation regulates astrocytic coupling strength. Furthermore, these animals showed significantly less seizure activity, demonstrating the importance of astrocytic coupling on the progression of TLE. However, incubation of acute brain slices from wildtype mice with TNF-alpha in situ revealed no impaired astrocytic coupling. Therefore, we suggest that a second mediator, like IL-1beta or a yet unknown molecule, might be needed to induce astrocytic uncoupling.
In conclusion, this study demonstrates that solTNF-alpha/TNFR1 mediates astrocytic uncoupling and plays a key role in the development of TLE-HS. Rescuing astrocytic coupling might represent a new strategy to develop antiepileptogenic therapies. The present project elucidated the therapeutic potential of targeting astrocytic proteins in epilepsy and also shed further light on the mechanisms underlying the disorder.},
url = {https://hdl.handle.net/20.500.11811/7647}
}
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