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Inhibition of the NMDA Currents by Probenecid in Amygdaloid Kindling Epilepsy Model

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Abstract

Epilepsy is characterized by a sustained depolarization and repeated discharge of neurons, attributed to overstimulation of N-methyl-D-aspartate receptors (NMDAr). Herein, we propose that probenecid (PROB), an inhibitor of the activity of some ATP binding-cassette transporters (ABC-transporters) can modify NMDAr activity and expression in amygdaloid kindled model. Some studies have suggested that NMDAr expression could be regulated by inhibiting the activity of P-glycoprotein (MDR1) and drug resistance protein-1 (MRP1). Besides, PROB was found to interact with other proteins with proven activity in the kindling model, such as TRPV2 channels, OAT1, and Panx1. Administering PROB at two doses (100 and 300 mg/kg/d) for 5 d decreased after-discharge duration and Racine behavioral scores. It also reduced the expression of NR2B and the activity of total NOS and the expression of nNOS with respect to the kindling group. In a second protocol, voltage-clamp measurements of NMDA-evoked currents were performed in CA1 hippocampal cells dissociated from control and kindled rats. PROB produced a dose-dependent reduction in NMDA-evoked currents. In neurons from kindled rats, a residual NMDA-evoked current was registered with respect to control animals, while a reduction in NMDA-evoked currents was observed in the presence of 20 mM PROB. Finally, we evaluated the expression of MRP1 and MDR1 in order to establish a relationship between the reduction of kindling parameters, the inhibition of NMDA-type currents, and the expression of these transporters. Based on our results, we conclude that at the concentrations used, PROB inhibits currents evoked by NMDA in dissociated neurons of control and kindled rats. In the kindling model, at the tested doses, PROB decreases the after-discharge duration and Racine behavioral score in the kindling model. We propose a mechanism that could be dependent on the expression of ABC-type transporters.

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Data Availability

The datasets used and/or analyses during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank Dr. Carlos Paz Tres for facilitating the infrastructure of his laboratory, Dr. Denise Campos-Arroyo for her supervision in the design and development of the semi-quantitative RT-PCR technique, Francisco Gutiérrez-Baeza by his technical support, and Juan Francisco Rodriguez for copyediting the manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Departamento de Neurofisiología, Instituto Nacional de Neurología y Neurocirugía MVS, Mexico City, 14629, México

    Edith González-Guevara, Esther Lara-González, Javier Franco-Pérez, Miguel Hernández-Cerón, Cesar Martínez-de los Santos, Verónica Custodio & Juan Carlos Martínez-Lazcano

  2. Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía MVS, Insurgentes Sur 3877, La Fama, Mexico City, 14629, México

    Edith González-Guevara, Francisca Pérez-Severiano & Juan Carlos Martínez-Lazcano

  3. División Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, 04510, México

    Esther Lara-González, Ernesto Rendon-Ochoa, Antonio Laville & José Bargas

  4. Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Esther Lara-González

  5. Laboratorio de Psicofarmacología, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, 54090, México

    Ernesto Rendon-Ochoa

  6. Laboratorio de Neuropatología Vascular, Instituto Nacional de Neurología y Neurocirugía MVS, Mexico City, 14629, México

    Javier Franco-Pérez

  7. Laboratorio de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía MVS, Mexico City, 14629, México

    Miguel Hernández-Cerón

  8. Departamento de Neuroanestesiología, Instituto Nacional de Neurología y Neurocirugía MVS, Mexico City, 14269, México

    Cesar Martínez-de los Santos

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  1. Edith González-Guevara
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Contributions

All authors contributed sufficiently for being credited as an author of this article. Conception and design: JCML, JFP and VC. JFP and MHC performed the stereotaxic surgery and the development of the kindling model. EGG and CMS performed the molecular experiments. ELG, ERO, and AL and JB performed the patch clamp experiment and data analysis. FPS performed the enzymatic activity experiment. VC provided technical support. EGG, ELG, and JCML performed data analysis. The first draft of the manuscript was written by JCML and all authors contributed to previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Juan Carlos Martínez-Lazcano.

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This study was conducted in accordance with the institutional guidelines and national regulation (NOM-062-ZOO-1999) from the Guide for the Care and Use of Laboratory Animals (8th edition), and international guiding principles (Council for International Organizations of Medical Sciences, CIOMS)

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González-Guevara, E., Lara-González, E., Rendon-Ochoa, E. et al. Inhibition of the NMDA Currents by Probenecid in Amygdaloid Kindling Epilepsy Model. Mol Neurobiol 61, 6264–6278 (2024). https://doi.org/10.1007/s12035-024-03969-0

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