Antiepileptic Drug Discovery: Novel Approaches

387 Pages·2016·8.919 MB·English

by  Alan Talevi, Luisa Rocha (eds.)

Methods in Pharmacology
and Toxicology
Alan Talevi
Luisa Rocha Editors
Antiepileptic
Drug Discovery
Novel Approaches
M P
ETHODS IN HARMACOLOGY
T
AND OXICOLOGY
Series Editor
Y. James Kang
University of Louisville
School of Medicine
Prospect, Kentucky, USA
For further volumes:
http://www.springer.com/series/7653

Antiepileptic Drug Discovery
Novel Approaches
Edited by
Alan Talevi
CONICET, National University of La Plata, La Plata, Argentina
Luisa Rocha
Department of Pharmacobiology, Center for Research and Advanced Studies,
Mexico City, Mexico
Editors
Alan Talevi Luisa Rocha
Laboratorio de Investigación y Desarrollo de Department of Pharmacobiology
Bioactivos (LIDeB) Faculty of Exact Sciences Center for Research and Advanced Studies
National University of La Plata Mexico City, Mexico
La Plata, Buenos Aires, Argentina
ISSN 1557-2153 ISSN 1940-6053 (electronic)
Methods in Pharmacology and Toxicology
ISBN 978-1-4939-6353-9 ISBN 978-1-4939-6355-3 (eBook)
DOI 10.1007/978-1-4939-6355-3
Library of Congress Control Number: 2016949635
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Prefa ce
Despite the introduction of several novel antiepileptic medications to the clinical practice
during the last 20 years, the proportion of patients failing to achieve a seizure-free status
has not improved substantially. Furthermore, current antiepileptic drugs provide symptom-
atic control to responsive patients (anticonvulsive or antiseizure effect) but have not proven
to prevent the setting and progression of the disorder (antiepileptogenesis). Leading experts
have emphasized the need for paradigm shifts in the fi eld of antiepileptic drug discovery as
a key factor to arrive at truly innovative therapeutic solutions. Such innovative solutions
involve a wide and multidisciplinary array of strategies, including, among others, the devel-
opment of new in vitro and in vivo models of epilepsy, the exploration of new molecular
targets and mechanisms of action, the integration of computer-aided approaches, and the
development of advanced drug delivery systems. Even though remarkable (yet incomplete)
progress has been made in the knowledge of the pathophysiology of epilepsy and the deter-
minants of refractoriness, these advancements have so far not crystallized into more effi ca-
cious therapeutic strategies. What is more, the epilepsy fi eld has fallen somewhat behind
regarding the integration of modern drug development tools, in comparison with other
complex disorders such as cancer or Alzheimer’s and Parkinson’s diseases.
This volume aims to provide medicinal chemists, pharmacologists, and other scientists
involved in antiepileptic drug discovery with a comprehensive view of novel approaches for
the development of antiepileptic therapies, with a focus on novel molecular targets for anti-
epileptic drugs, computer-aided approaches for the identifi cation of new drug candidates,
and therapeutic strategies to overcome refractory epilepsy. The last part illustrates the
potential benefi ts that network pharmacology and rational drug repurposing could bring to
the antiepileptic drug discovery community.
The volume is made up of 19 chapters that are briefl y commented on next.
Firstly, López-Meraz et al. describe the role of proinfl ammatory cytokines in the neu-
roinfl ammation process associated with seizure activity. They indicate the relevance of con-
sidering these cytokines as potential therapeutic targets for the pharmacological treatment
of epilepsy. Valle-Dorado et al. present a review of different anti-infl ammatory drugs that
may be used to avoid the neuroinfl ammation that results from seizure activity. These authors
suggest that anti-infl ammatory drugs represent a strategy to decrease the higher excitability
associated with epilepsy. Mendoza-Torreblanca et al. describe some of the basic aspects of
the role of synaptic vesicle protein 2A (SV2A) in epilepsy, and support that this molecule is
a good molecular target for the design of new antiepileptic drugs. Interestingly, they also
provide an immunochemical protocol to obtain reliable semi-quantitative data of SV2A as
well as a methodology to develop SV2A molecular dynamics simulations. Zavala and Rocha
explain the relevance of evaluating the pro- and anticonvulsant effects of cannabinoids,
depending on the type of epilepsy and the rate of excitability. Cuellar-Herrera et al. examine
the importance of the pharmacological blockade of glutamate receptors as a therapeutic
strategy to control seizure activity and induce neuroprotection. Gavernet discusses the
existing evidence of the potential use of carbonic anhydrase as an antiepileptic drug target,
describing a structure-based procedure for the design of novel inhibitors. Joshi and Kapur
v
vi Preface
describe experimental evidence supporting the idea that neurosteroids regulate seizure
activity via modulation of GABA receptors. They also provide data that neurosteroids rep-
A
resent a novel target to control seizure activity in women with epilepsy. Marelli et al. describe
the mechanisms involved in the neuroprotective effects induced by erythropoietin and pro-
pose that the activation of its receptor (EPO receptor) can be used as a therapeutic strategy
to avoid epileptogenesis and pharmacoresistant epilepsy. The last two chapters of the fi rst
part of the volume are dedicated to treatment options different from traditional small mol-
ecule therapies. Carvajal Aguilera and Phillips Farfán review different eating regimes used
to control seizure activity and the mechanisms involved in their effects. They propose that
elucidating the underlying mechanisms of these therapeutic interventions could help in the
development of innovative antiepileptic medications, and they provide a protocol for the
preclinical study of caloric restriction. López-García et al. provide a review of different gene
therapies considered as possible strategies to reduce seizure activity.
In the second part, Lara et al. present an overview of the relevance of using human
brain tissue to evaluate the pharmacoresistance in epilepsy and describe protocols of differ-
ent approaches to fulfi ll this goal: in vitro electrophysiological recordings, in vitro proce-
dures for receptor evaluation, and genomic analyses. Rogel-Salazar and Luna-Munguia
analyze the role of the blood-brain barrier in epilepsy and the relevance of considering this
structure as a target to design new antiepileptic strategies. Talevi and Bruno-Blanch describe
the general procedures to implement a ligand-based virtual screening campaign for the
identifi cation of novel antiepileptic drugs. Couyoupetrou et al. also discuss technical aspects
of computational (ligand-based) and experimental approaches used for the early detection
of substrates of effl ux systems, which could assist in the development of new antiepileptic
drugs addressing the transporter hypothesis of pharmacoresistant epilepsy. Similarly,
Palestro and Gavernet describe structure-based approaches that can be used to predict
P-glycoprotein substrates. At the end of the second part of the volume, Ruiz and Castro
examine the potential use of pharmaceuticals’ micro- and nanocarriers to improve central
nervous system bioavailability of antiepileptic agents; they also provide an experimental
procedure to study drug release from such advanced pharmaceutical vehicles in vitro.
In the last part, Kubova presents a review of the different side effects induced by the
different antiepileptic drugs and points out the necessity to carry out comparative, well-
designed, and long-term trials in order to identify the best pharmacological strategy to
control epilepsy. This author also emphasizes some reported benefi cial effects of known
antiepileptic drugs on comorbid mood disorders. In the two fi nal chapters of the book,
Talevi discusses the potential of network pharmacology and drug repurposing in the fi eld
of antiepileptic drug discovery, along with some practical consideration on how these
approaches could be integrated into the drug discovery process.
The editors consider this book to be an excellent tool for the study of pharmacoresis-
tant epilepsy and the discovery of new antiepileptic drugs.
Alan Talevi
Luisa Rocha
Contents
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i x
PART I NOVEL APPROACHES FOR THE TREATMENT OF EPILEPSY
1 I nflammatory Cytokines as Targets for Epilepsy Drug Therapy . . . . . . . . . . . . 3
María-Leonor López-Meraz , J esús-Servando Medel-Matus ,
and Jerome Niquet
2 T he Use of Anti-inflammatory Drugs in Epilepsy . . . . . . . . . . . . . . . . . . . . . . 2 3
María Guadalupe Valle-Dorado , L aura Elena Córdova-Dávalos ,
Daniel Pérez-Pérez , R osalinda Guevara-Guzmán , and Luisa Rocha
3 C arbonic Anhydrase and Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 7
Luciana Gavernet
4 S ynaptic Vesicle Protein 2A as a Novel Pharmacological Target
with Broad Potential for New Antiepileptic Drugs. . . . . . . . . . . . . . . . . . . . . . 53
Luz Adriana Pichardo-Macías, Itzel Jatziri Contreras-García,
Sergio R. Zamudio, Edgar Mixcoha, and Julieta G. Mendoza-Torreblanca
5 D o Cannabinoids Represent a Good Therapeutic Strategy for Epilepsy? . . . . . 8 3
Cecilia Zavala-Tecuapetla and Luisa Rocha
6 G lutamate Receptors as Targets for Novel Antiepileptic Drug Therapy . . . . . . 9 7
Manola Cuéllar-Herrera , C ésar E. Santana-Gómez ,
Francia Carmona-C ruz , D aruni Vázquez-Barrón , F rancisco Velasco ,
and Ana L. Velasco
7 N eurosteroid Regulation of Seizures: Role of GABAA Receptor Plasticity. . . . 1 27
Suchitra Joshi and Jaideep Kapur
8 E rythropoietin as Potential Neuroprotective and Antiepileptogenic
Agent in Epilepsy and Refractory Epilepsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Amalia Marelli , L iliana Czornyj , L uisa Rocha , and Alberto Lazarowski
9 C aloric Restriction and Dietary Treatments of Epilepsy:
Mechanistic Insights for Drug Discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Karla G. Carvajal Aguilera and Bryan V. Phillips Farfán
1 0 G ene Therapy in Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 81
Miguel A. López-García , I ris A. Feria-Romero , J ulia J. Segura-Uribe ,
David Escalante-S antiago , and Sandra Orozco-Suárez
vii
viii Contents
PART II I NNOVATIVE SOLUTIONS FOR THE SCREENING
OF NEW ANTIEPILEPTICS DRUGS AND ADDRESSING
MULTI-DRUG RESISTANT EPILEPSY
11 H uman Brain Tissue as a Model for the Study of Epilepsy. . . . . . . . . . . . . . . . 2 03
Leonardo Lara-Valderrábano , I vette Bañuelos-Cabrera ,
Víctor Navarrete-Modesto , and Luisa Rocha
12 T he Blood–Brain Barrier and the Design of New Antiepileptic Drugs . . . . . . . 2 21
Gabriela Rogel-Salazar and Hiram Luna-Munguia
13 V irtual Screening Applications in the Search of Novel Antiepileptic
Drug Candidates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Alan Talevi and Luis E. Bruno-Blanch
14 D iscovering New Antiepileptic Drugs Addressing the Transporter
Hypothesis of Refractory Epilepsy: Ligand- Based Approximations. . . . . . . . . . 259
Manuel Couyoupetrou , M auricio Di Ianni , M elisa Gantner ,
Guido Pesce , R oxana Peroni , A lan Talevi , and Luis E. Bruno-Blanch
15 D iscovering New Antiepileptic Drugs Addressing the Transporter
Hypothesis of Refractory Epilepsy: Structure-Based Approximations. . . . . . . . 281
Pablo Palestro and Luciana Gavernet
16 N anoformulations of Antiepileptic Drugs: In Vitro and In Vivo Studies. . . . . . 2 99
María E. Ruiz and Guillermo R. Castro
PART III POTENTIAL CONTRIBUTIONS OF NETWORK PHARMACOLOGY
AND DRUG REPURPOSING IN ANTIEPILEPTIC DRUG DISCOVERY
17 S ide Effects of Antiepileptic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 29
Hana Kubova
18 N etwork Pharmacology and Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 51
Alan Talevi
19 T he Importance of Drug Repurposing in the Field of Antiepileptic
Drug Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Alan Talevi
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
Contributors
IVETTE BAÑUELOS-CABRERA • Department of Pharmacobiology , C enter for Research
and Advanced Studies , M exico City, M exico
LUIS E. BRUNO-BLANCH • Laboratorio de Investigación y Desarrollo de Bioactivos (LIDeB),
Faculty of Exact Sciences, N ational University of La Plata , L a Plata, B uenos Aires,
Argentina
FRANCIA CARMONA-CRUZ • Department of Pharmacobiology , C enter for Research and
Advanced Studies , M exico City, M exico
KARLA G. CARVAJAL AGUILERA • Laboratorio de Nutrición Experimental, I nstituto
Nacional de Pediatría , M exico City, M exico
GUILLERMO R. CASTRO • Nanobiomaterials Laboratory , A pplied Biotechnology Institute
(CINDEFI, UNLP-CONICET CCT La Plata) -School of Sciences, Universidad
Nacional de La Plata , L a Plata, A rgentina
ITZEL JATZIRI CONTRERAS-GARCÍA • Laboratorio de Neurociencias, I nstituto Nacional de
Pediatría , M exico City, M exico ; U niversidad Autónoma Metropolitana , M exico City,
Mexico
LAURA ELENA CÓRDOVA-DÁVALOS • Department of Physiology, Faculty of Medicine,
National Autonomous University of Mexico , M exico City, M exico
MANUEL COUYOUPETROU • Laboratorio de Investigación y Desarrollo de Bioactivos
(LIDeB), Faculty of Exact Sciences, N ational University of La Plata , L a Plata, B uenos
Aires, A rgentina ; A dministración Nacional de Medicamentos, Alimentos y Tecnología
Médica (ANMAT) , I nstituto Nacional de Medicamentos (INAME) , B uenos Aires,
Argentina
MANOLA CUÉLLAR-HERRERA • Epilepsy Clinic, Unit of Functional Neurosurgery, Stereotaxy
and Radiosurgery , G eneral Hospital of Mexico “Dr. Eduardo Liceaga” , M exico City,
Mexico
LILIANA CZORNYJ • Fundación INVESTIGAR , C ABA , A rgentina ; N eurology Service ,
National Pediatric Hospital “Juan P Garrahan” , C ABA , A rgentina
DAVID ESCALANTE-SANTIAGO • Unidad de Investigación Médica en Enfermedades
Neurológicas, Hospital de Especialidades Centro Médico Nacional Siglo XXI , I nstituto
Mexicano del Seguro Social , M exico City, M exico
IRIS A. FERIA-ROMERO • Unidad de Investigación Médica en Enfermedades Neurológicas,
Hospital de Especialidades Centro Médico Nacional Siglo XXI , I nstituto Mexicano del
Seguro Social , M exico City, M exico
MELISA GANTNER • Laboratorio de Investigación y Desarrollo de Bioactivos (LIDeB),
Faculty of Exact Sciences, N ational University of La Plata , L a Plata, B uenos Aires,
Argentina
LUCIANA GAVERNET • Laboratory of Bioactive Research and Development (LIDeB),
Department of Biological Sciences, Faculty of Exact Sciences, U niversity of La Plata ,
La Plata, B uenos Aires, A rgentina
ROSALINDA GUEVARA-GUZMÁN • Department of Physiology, Faculty of Medicine, N ational
Autonomous University of Mexico , M exico City, M exico
ix