Anticonvulsive Activity in Audiogenic DBA/2 Mice of 1,4-Benzodiazepines and 1,5-Benzodiazepines with Different Activities at Cerebellar Granule Cell GABA_A Receptors

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• 作者：Elena Gatta ; Aroldo Cupello ; Mario Di Braccio…
• 关键词：1 ; 4 ; Benzodiazepines and 1 ; 5 ; benzodiazepines ; Cerebellar granule cells ; Audiogenic DBA/2 mice ; Epilepsy ; Cerebellum ; Anticonvulsive action
• 刊名：Journal of Molecular Neuroscience
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：60
• 期：4
• 页码：539-547
• 全文大小：624 KB
• 刊物主题：Neurosciences; Neurochemistry; Cell Biology; Proteomics; Neurology;
• 出版者：Springer US
• ISSN：1559-1166
• 卷排序：60

文摘

Herein, we tested in a model of generalized reflex epilepsy in mice different 1,4-benzodiazepines and 1,5-benzodiazepines with agonistic activity at the GABA_A receptor population contributing to the peak component of the chloride current elicited by GABA in cerebellar granule cells (CGCs) in culture. The substances have all higher lipophilia than clobazam, an antiepileptic drug well known and used in human therapy. This ensures that they all can pass relatively easily the blood-brain barrier (BBB). The benzodiazepines were administered intraperitoneally (i.p.) and tested for their activity against sound-induced tonic and clonic seizures in a genetic model of experimental epilepsy, the DBA/2 mouse. Our data demonstrates an interesting inverse correlation between the ED₅₀s and the efficacy (E %) of the drugs in increasing the peak chloride current elicited by GABA in cerebellar granule cells in culture. There is indication of the existence of a threshold of E % above which the increase of ED₅₀ with increasing E % becomes linear. This is statistically significant for the clonic phase, whereas it is at the limit of significance for the tonic one. A possible interpretation of these results is that in this epilepsy model, projections from the cerebellum exert a convulsion prevention activity.