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Finding a better drug for epilepsy: Preclinical screening strategies and experimental trial design

Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Ferrara, and National Institute of Neuroscience, Ferrara, Italy Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine and Center for Systems Neuroscience, Hannover, Germany Epilepsy Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Department of Physiology, Salk School of Medicine, University of Utah, Salt Lake City, Utah, U.S.A. Departments of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences, and the Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. CNS Research, UCB Pharma, Braine-l'Alleud, Belgium Wayne State University, Detroit, Michigan, U.S.A. New York University Langone Medical Center and Colombia University, New York, New York, U.S.A. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Departments of Cell Biology & Anatomy, and Pediatrics, New York Medical College, Valhalla, New York, U.S.A.
Epilepsia (Impact Factor: 4.58). 06/2012; 53(11). DOI: 10.1111/j.1528-1167.2012.03541.x
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ABSTRACT The antiepileptic drugs (AEDs) introduced during the past two decades have provided several benefits: they offered new treatment options for symptomatic treatment of seizures, improved ease of use and tolerability, and lowered risk for hypersensitivity reactions and detrimental drug-drug interactions. These drugs, however, neither attenuated the problem of drug-refractory epilepsy nor proved capable of preventing or curing the disease. Therefore, new preclinical screening strategies are needed to identify AEDs that target these unmet medical needs. New therapies may derive from novel targets identified on the basis of existing hypotheses for drug-refractory epilepsy and the biology of epileptogenesis; from research on genetics, transcriptomics, and epigenetics; and from mechanisms relevant for other therapy areas. Novel targets should be explored using new preclinical screening strategies, and new technologies should be used to develop medium- to high-throughput screening models. In vivo testing of novel drugs should be performed in models mimicking relevant aspects of drug refractory epilepsy and/or epileptogenesis. To minimize the high attrition rate associated with drug development, which arises mainly from a failure to demonstrate sufficient clinical efficacy of new treatments, it is important to define integrated strategies for preclinical screening and experimental trial design. An important tool will be the discovery and implementation of relevant biomarkers that will facilitate a continuum of proof-of-concept approaches during early clinical testing to rapidly confirm or reject preclinical findings, and thereby lower the risk of the overall development effort. In this review, we overview some of the issues related to these topics and provide examples of new approaches that we hope will be more successful than those used in the past.

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    • "Therapy resistance represents a major issue in the management of epilepsy. Diverse potential mechanistic causes have been proposed [1] [2] [3] [4], and new experimental approaches have been established in order to discover therapies providing better efficacy [5] [6]. Nevertheless, a clear medical need remains in order to achieve complete seizure control in a substantial population of patients with treatmentresistant epilepsy [7]. "
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    ABSTRACT: Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be time-consuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (d,l)-Allylglycine inhibits glutamic acid decarboxylase (GAD) - the key enzyme in γ-aminobutyric acid (GABA) biosynthesis - leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated cross-species similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures. Copyright © 2015 Elsevier Inc. All rights reserved.
    Epilepsy & Behavior 04/2015; 45. DOI:10.1016/j.yebeh.2015.03.019 · 2.06 Impact Factor
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    • "Therapy resistance represents a major issue in the management of epilepsy. Diverse potential mechanistic causes have been proposed [1] [2] [3] [4], and new experimental approaches have been established in order to discover therapies providing better efficacy [5] [6]. Nevertheless, a clear medical need remains in order to achieve complete seizure control in a substantial population of patients with treatmentresistant epilepsy [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be timeconsuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (D,L)-Allylglycine inhibits glutamic acid decarboxylase (GAD) – the key enzyme in γ-aminobutyric acid (GABA) biosynthesis – leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated crossspecies similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.
    Epilepsy & Behavior 03/2015; 45:53-63. · 2.06 Impact Factor
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    • "There is an emerging consensus that biomarkers would be useful diagnostics in epilepsy (Pitkanen and Lukasiuk, 2011b; Simonato et al., 2012; Engel et al., 2013a). Molecular biomarkers of SE could be used to gauge insult severity, prognosis, and inform the choice of anticonvulsants or administration of anti-epileptogenic treatments, were they to become available. "
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    ABSTRACT: MicroRNA (miRNA) are an important class of non-coding RNA which function as post-transcriptional regulators of gene expression in cells, repressing and fine-tuning protein output. Prolonged seizures (status epilepticus, SE) can cause damage to brain regions such as the hippocampus and result in cognitive deficits and the pathogenesis of epilepsy. Emerging work in animal models has found that SE produces select changes to miRNAs within the brain. Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE. The miRNA changes that accompany SE are predicted to impact levels of multiple proteins involved in neuronal morphology and function, gliosis, neuroinflammation, and cell death. miRNA expression also displays select changes in the blood after SE, supporting blood genomic profiling as potential molecular biomarkers of seizure-damage or epileptogenesis. Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs. Targeting miR-34a, miR-132 and miR-184 has been reported to alter seizure-induced neuronal death, whereas targeting miR-134 was neuroprotective, reduced seizure severity during status epilepticus and reduced the later emergence of recurrent spontaneous seizures. These studies support roles for miRNAs in the pathophysiology of status epilepticus and miRNAs may represent novel therapeutic targets to reduce brain injury and epileptogenesis.
    Frontiers in Molecular Neuroscience 11/2013; 6:37. DOI:10.3389/fnmol.2013.00037 · 4.08 Impact Factor
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