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

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Abstract

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 GABAA 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.

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Authors and Affiliations

  1. Department of Physics, University of Genova, Via Dodecaneso 33, 16146, Genoa, Italy

    Elena Gatta, Aroldo Cupello & Mauro Robello

  2. Department of Pharmacy, Pharmaceutical Chemistry Section, University of Genova, 16132, Genoa, Italy

    Mario Di Braccio & Giancarlo Grossi

  3. Science of Health Department, School of Medicine, University “Magna Graecia” of Catanzaro, 88100, Catanzaro, Italy

    Francesca Scicchitano, Emilio Russo & Giovambattista De Sarro

Authors
  1. Elena Gatta
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  2. Aroldo Cupello
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  3. Mario Di Braccio
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  4. Giancarlo Grossi
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  5. Mauro Robello
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  6. Francesca Scicchitano
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  7. Emilio Russo
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  8. Giovambattista De Sarro
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Correspondence to Aroldo Cupello.

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Gatta, E., Cupello, A., Di Braccio, M. et al. Anticonvulsive Activity in Audiogenic DBA/2 Mice of 1,4-Benzodiazepines and 1,5-Benzodiazepines with Different Activities at Cerebellar Granule Cell GABAA Receptors. J Mol Neurosci 60, 539–547 (2016). https://doi.org/10.1007/s12031-016-0838-0

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  • DOI: https://doi.org/10.1007/s12031-016-0838-0

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