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The anticonvulsant actions of novel ’broad-spectrum’ Ca2+ channel blockers and low affinity, uncompetitive NMDA receptor antagonists Thurgur, Claire Helen
Abstract
Epilepsy is a prominent neurological disorder. Presently available anticonvulsant drugs however fail to alleviate seizures in approximately 25% of individuals, and are often accompanied by serious side effects. More efficacious and less toxic agents are required. In this study, the effects of a range of structurally dissimilar a site ligands were examined against evoked and spontaneous epileptiform activity induced in rat hippocampal slices by perfusion with Mg2+-free medium. Extracellular recordings were made in the CA1 hippocampal region of epileptiform activity evoked by stimulation of the Schaffer collateral (SC) pathway, and of spontaneous epileptiform activity originating from the CA3 hippocampal region. Evoked and spontaneous epileptiform activity was inhibited by all compounds tested with the rank order (IC5 0 values against evoked epileptiform activity in uM): dextrorphan (2) > ifenprodil (6) > dextromethorphan (10) > l,3-di(2-tolyl)guanidine (15) > loperamide (28) > carbetapentane (38) > caramiphen (46) > opipramol (52). Ifenprodil, loperamide, caramiphen and dextrorphan were also examined for their effects on the input/output (I/O) functions along the SC pathway and on the paired pulse facilitation (PPF) ratio. An effect was observed only in the presence of caramiphen, which showed a decrease in the synaptic transmission I/O function and reduced markedly the PPF ratio. The (micromolar) concentrations required for the anticonvulsant activity of the CT ligands tested suggests that their anticonvulsant actions are not mediated by high affinity (nanomolar) binding to rj binding sites, but rather to blockade of high voltage activated Ca2 + channels and/or NMD A receptors, actions which occur at micromolar concentrations.
Item Metadata
Title |
The anticonvulsant actions of novel ’broad-spectrum’ Ca2+ channel blockers and low affinity, uncompetitive NMDA receptor antagonists
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
1996
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Description |
Epilepsy is a prominent neurological disorder. Presently available anticonvulsant drugs
however fail to alleviate seizures in approximately 25% of individuals, and are often
accompanied by serious side effects. More efficacious and less toxic agents are required. In
this study, the effects of a range of structurally dissimilar a site ligands were examined against
evoked and spontaneous epileptiform activity induced in rat hippocampal slices by perfusion
with Mg2+-free medium. Extracellular recordings were made in the CA1 hippocampal region
of epileptiform activity evoked by stimulation of the Schaffer collateral (SC) pathway, and of
spontaneous epileptiform activity originating from the CA3 hippocampal region. Evoked and
spontaneous epileptiform activity was inhibited by all compounds tested with the rank order
(IC5 0 values against evoked epileptiform activity in uM): dextrorphan (2) > ifenprodil (6) >
dextromethorphan (10) > l,3-di(2-tolyl)guanidine (15) > loperamide (28) > carbetapentane
(38) > caramiphen (46) > opipramol (52). Ifenprodil, loperamide, caramiphen and dextrorphan
were also examined for their effects on the input/output (I/O) functions along the SC pathway
and on the paired pulse facilitation (PPF) ratio. An effect was observed only in the presence of
caramiphen, which showed a decrease in the synaptic transmission I/O function and reduced
markedly the PPF ratio. The (micromolar) concentrations required for the anticonvulsant
activity of the CT ligands tested suggests that their anticonvulsant actions are not mediated by
high affinity (nanomolar) binding to rj binding sites, but rather to blockade of high voltage
activated Ca2 + channels and/or NMD A receptors, actions which occur at micromolar
concentrations.
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Extent |
6538296 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-03-07
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0087605
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
1997-05
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
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Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.