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Tolerance to the anticonvulsant effects of clobazam in mice
1Department of Physiological Sciences, University of Manchester, U.K.
Abstract:
Tolerance to the anticonvulsant effects of clobazam has been studied in three murine models of epilepsy: pentylenetetrazole- and N-methyl-D,L-aspartic acid-induced seizures and audiogenic-induced seizures in the DBA/2 strain. Tolerance occurred most rapidly in the pentylenetetrazole model but the development of tolerance could be reduced by increasing the dose interval. Tolerance to the protective effects of clobazam occurred more readily to the first tonic seizure than to the full tonic clonic seizure. The development of tolerance could not be attributed to smaller concentrations of clobazam in brain or to increasing concentrations of the metabolite. Although slower to develop, tolerance to clobazam did occur in the N-methyl-D,L-aspartate model. However, tolerance to the protection from the full tonic clonic seizure in DBA/2 mice could not be detected, even when the dose of clobazam was reduced to the smallest dose that acutely protected most of the mice. In contrast, the protection given by clobazam to the induction of the wild-run in DBA/2 mice, did exhibit tolerance. Studies on the mechanism of tolerance to the anticonvulsant activity of benzodiazepines must take account of the seizure model used and the dose and interval between doses.
Insights
Tolerance to clobazam, an anticonvulsant, varies by epilepsy model. Researchers found tolerance developed fastest in pentylenetetrazole-induced seizures, but could be slowed by adjusting dosage intervals. Factors like seizure type and dosing schedule influence tolerance development.
Area of Science:
- Pharmacology
- Neuroscience
- Epileptology
Background:
- Anticonvulsant medications like clobazam are crucial for epilepsy management.
- Understanding tolerance to anticonvulsants is essential for optimizing long-term treatment efficacy.
- Benzodiazepines, including clobazam, are widely used but can be subject to tolerance development.
Purpose of the Study:
- To investigate the development of tolerance to the anticonvulsant effects of clobazam across different murine epilepsy models.
- To determine factors influencing the rate and extent of clobazam tolerance.
- To examine the relationship between clobazam concentration, metabolite levels, and tolerance.
Main Methods:
- Evaluated clobazam efficacy in three distinct epilepsy models: pentylenetetrazole-induced seizures, N-methyl-D,L-aspartate-induced seizures, and audiogenic seizures in DBA/2 mice.
- Assessed tolerance by monitoring seizure occurrence and severity after repeated clobazam administration.
- Measured clobazam and its metabolite concentrations in brain tissue.
Main Results:
- Tolerance to clobazam developed most rapidly in the pentylenetetrazole model, with dose interval influencing the rate.
- Tolerance was more pronounced for the first tonic seizure compared to the full tonic-clonic seizure.
- No significant tolerance to full tonic-clonic seizures was observed in DBA/2 mice, but tolerance to the wild-run seizure did occur.
- Tolerance development could not be explained by altered clobazam or metabolite concentrations in the brain.
Conclusions:
- The development of tolerance to clobazam is dependent on the specific seizure model and the type of seizure observed.
- Factors such as dose frequency and the nature of the seizure endpoint significantly impact tolerance.
- Future studies on benzodiazepine tolerance must consider the nuances of the experimental model and dosing parameters.