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The Calcineurin Inhibitor Ascomicin Interferes with the Early Stage of the Epileptogenic Process Induced by Latrunculin A Microperfusion in Rat Hippocampus

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Abstract

Latrunculin A microperfusion in rat hippocampus has shown to be an effective model of acute and chronic seizures for neurochemical studies. The intervention over early synaptic plasticity changes after the epileptogenesis onset represents a big challenge on the design of a suitable therapy to impair the epilepsy development. We previously suggested that receptor location might be essential for controlling neuronal excitability, and that disruption of local cytoskeletal dynamics followed by drastic changes in the synaptic/extrasynaptic ratio of NMDA, AMPA receptors and their subsequent downstream signalling may play an important role in the pathogenesis of seizures. In the present study, we performed a pharmacological intervention in the Latrunculin model by using Ascomicin (ASC) and Phenytoin (PHT). We pointed out the inhibitory action of ASC over the protein phosphatase 2B (PP2B). PP2B pathological mechanism involves changes in actin cytoskeleton and showed to avoid those subsequent changes previously observed in PSD components. On the contrary, PHT didn’t seem to modify the F-actin depolymerization process induced, showing a similar redistribution pattern from the PSD towards the extrasynaptic site of several molecular components with more or less dependence on actin for their location, including glutamate receptors. Overall, we propose that the early intervention over changes on the synapse during the epileptogenic process might represent the best approach to avoid the onset of chronic refractory seizures our model. On this regard, the therapeutic potential of ASC, FK506 and derivatives should be further explored as a possible tool in the intervention over epilepsy and other brain diseases.

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Acknowledgments

This work was supported by grant XUGA PGIDT00PXI20807PR and XUGA PGIDIT03PXIB20803PR from the Consellería de Educación e Ordenación Universitaria, Xunta de Galicia, Spain.

Thanks Dr. Sierra Marcuño for the dedication of your life to science. You have left valuable contributions in your laboratory works, medical practice and education during your whole lifetime, your memory will always live with us in our daily work.

Disclosure

The authors have no conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain

    Carmen Freire-Cobo, Germán Sierra-Paredes & Germán Sierra-Marcuño

  2. Department of Biochemistry and Molecular Biology, School of Biology, University of Santiago de Compostela, Santiago de Compostela, Spain

    Carmen Freire-Cobo & Manuel Freire

  3. Carmen Freire-Cobo, Brain & Behavior Discovery Institute CL-3020, Georgia Regents University, Augusta, GA, 30912, USA

    Carmen Freire-Cobo

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  1. Carmen Freire-Cobo
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  2. Germán Sierra-Paredes
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  3. Manuel Freire
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Correspondence to Carmen Freire-Cobo.

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Freire-Cobo, C., Sierra-Paredes, G., Freire, M. et al. The Calcineurin Inhibitor Ascomicin Interferes with the Early Stage of the Epileptogenic Process Induced by Latrunculin A Microperfusion in Rat Hippocampus. J Neuroimmune Pharmacol 9, 654–667 (2014). https://doi.org/10.1007/s11481-014-9558-9

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