New anticonvulsant candidates prevent P-glycoprotein (P-gp) overexpression in a pharmacoresistant seizure model in mice Andrea Verónica Enrique a , Mauricio Emiliano Di Ianni a , Sofía Goicoechea a , Alberto Lazarowski b , María Guadalupe Valle-Dorado d , Juan José López Costa c , Luisa Rocha d , Elena Girardi c , Alan Talevi a, ⁎ a Laboratorio de Investigación y Desarrollo de Bioactivos (LIDeB), Departamento de Ciencias Biologicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP), 47 y115, La Plata B1900BJW, Argentina b Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Facultad de Farmacia y Bioquímica (FFyB), Universidad de Buenos Aires (UBA,) Junín 956, C1113AAD CABA, Argentina c Departamento de Biología Celular, Histología, Embriología y Genética, Facultad de Medicina, Universidad de Buenos Aires (UBA) / Instituto de Biología Celular y Neurociencia “Prof. E. De Robertis” (IBCN), CONICET-Universidad de Buenos Aires, Paraguay 2155, C1121ABG, Buenos Aires, Argentina d Department of Pharmacobiology, Center for Research and Advanced Studies (CINVESTAV), Mexico City, Mexico abstract article info Article history: Received 5 May 2019 Revised 17 July 2019 Accepted 19 July 2019 Available online xxxx Despite the approval of a considerable number of last generation antiepileptic drugs (AEDs) (only in the last de- cade, six drugs have gained Food and Drug Administration approval), the global figures of seizure control have seemingly not improved, and available AED can still be regarded as symptomatic treatments. Fresh thinking in AEDs drug discovery, including the development of drugs with novel mechanisms of action, is required to achieve truly innovative antiepileptic medications. The transporter hypothesis proposes that inadequate penetration of AEDs across the blood–brain barrier, caused by increased expression of efflux transporters such as P-glycoprotein (P-gp), contributes to drug-resistant epi- lepsy. Neuroinflammation due to high levels of glutamate has been identified as one of the causes of P-gp upreg- ulation, and several studies in animal models of epilepsy suggest that antiinflammatory drugs might prevent P-gp overexpression and, thus, avoid the development of refractory epilepsy. We have applied ligand-based in silico screening to select compounds that exert dual anticonvulsant and antiinflammatory effects. Five of the hits were tested in animal models of seizure, with protective effects. Later, two of them (sebacic acid (SA) and gamma-decanolactone) were submitted to the recently described MP23 model of drug-resistant seizures. All in all, SA displayed the best profile, showing activity in the maximal electro- shock seizure (MES) and pentylenetetrazol (PTZ) seizure models, and reversing resistance to phenytoin (PHT) and decreasing the P-gp upregulation in the MP23 model. Furthermore, pretreatment with SA in the pilocarpine status epilepticus (SE) model resulted in decreased histamine release in comparison with nontreated animals. This is the first report of the use of the MP23 model to screen for novel anticonvulsant compounds that may avoid the development of P-gp-related drug resistance. © 2019 Elsevier Inc. All rights reserved. Keywords: MP23 model Refractory epilepsy Inflammation P-glycoprotein Sebacic acid Ketogenic diet 1. Introduction Epilepsy is one of the most common chronic disorders of the brain, characterized by an enduring predisposition to generate epileptic sei- zures. Throughout the last three decades, the approval of more than fif- teen third-generation antiepileptic drugs (AEDs) has provided physicians and patients with numerous options to treat different types of epilepsies [1]. However, although approximately 70% of the patients with epilepsy eventually achieve symptomatic control or remission using the available AEDs, these medications fail to control seizures in around 30% of epilepsy cases [2,3]. In addition, existing drugs act mostly at a symptomatic level [4,5]. There is, therefore, an urgent need for new drugs capable of overcoming drug resistance issues and, if possible, pre- vent disease progression. The need of fresh thinking to revitalize the pharmacological and clin- ical development of better antiepileptic medications has been recog- nized by leading experts in the field [6]. The use of a systems biology perspective has been suggested to achieve innovative treatments [7,8], including, among other strategies, the development of multitarget agents and focusing on new drugs targeting the underlying causes of ep- ilepsy and drug resistance (e.g., neuroinflammation). One of the most extensively explored hypotheses to explain refrac- tory epilepsy is that drug resistance may be related to the overexpres- sion of ATP-Binding Cassette (ABC) transporters (among them P- glycoprotein (P-gp)) at the blood–brain barrier (BBB) and the seizure Epilepsy & Behavior xxx (xxxx) xxx ⁎ Corresponding author. E-mail address: atalevi@biol.unlp.edu.ar (A. Talevi). YEBEH-106451; No of Pages 10 https://doi.org/10.1016/j.yebeh.2019.106451 1525-5050/© 2019 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh Please cite this article as: A.V. Enrique, M.E. Di Ianni, S. Goicoechea, et al., New anticonvulsant candidates prevent P-glycoprotein (P-gp) overexpression in a pharmacoresistant se..., Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.106451