Antiepileptic Drug Discovery

White, H. Steve; Barker‐Haliski, Melissa

doi:10.1002/9781118936979.ch4

Cited by 6 publications

(5 citation statements)

References 75 publications

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“…3.1 | CBD demonstrates acute antiseizure efficacy following intraperitoneal administration in a battery of well-established acute rodent seizure models CBD (intraperitoneal [IP]) was initially evaluated for acute antiseizure efficacy in a battery of well-defined rodent seizure and epilepsy models ( Table 1). These models have formed the basis for ASD discovery for decades 17,18 and were thus employed to initially define the acute antiseizure efficacy of CBD relative to standard ASDs. 17 For the purposes of the present study, we have also included the efficacy data for the ASDs phenobarbital (PB), valproic acid (VPA), and felbamate (FBM) as reported in the National Institute of Neurological Disorders and Stroke public database PANAChE ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models

et al. 2018

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Summary Objective Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol ( CBD ) in a battery of acute seizure models. Additionally, we defined the disease‐modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus–spontaneous recurrent seizures ( RISE ‐ SRS ) model of temporal lobe epilepsy ( TLE ). Methods We evaluated the acute antiseizure effect of CBD in the maximal electroshock seizure, 6‐Hz psychomotor seizure, and pentylenetetrazol acute seizure tests, as well as the corneal kindling model of chronic seizures in mice following intraperitoneal administration. Median effective or behavioral toxic dose was determined in both mice and rats. Next, we tested an intravenous preparation of CBD (10 mg/kg single dose) in a rat model of pilocarpine‐induced status epilepticus. We defined the effect of chronic CBD administration (200 mg/kg orally) on spontaneous seizures, motor control, gait, and memory function in the rat RISE ‐ SRS model of TLE . Results CBD was effective in a battery of acute seizure models in both mice and rats following intraperitoneal administration. In the pilocarpine‐induced status epilepticus rat model, CBD attenuated maximum seizure severity following intravenous administration, further demonstrating CBD 's acute antiseizure efficacy in this rat model. We established that oral CBD attenuated the time‐dependent increase in seizure burden and improved TLE ‐associated motor comorbidities of epileptic rats in the RISE ‐ SRS model without affecting gait. Chronic administration of CBD after the onset of SRS ameliorated reference memory and working memory errors of epileptic animals in a spatial learning and memory task. Significance The present study illustrates that CBD is a well‐tolerated and effective antiseizure agent and illustrates a potential disease‐modifying effect of CBD on reducing both seizure burden and associated comorbidities well after the onset of symptomatic seizures in a model of TLE .

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Section: Resultsmentioning

confidence: 99%

Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models

et al. 2018

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“…20 Furthermore, the principles for each model should be sufficient to expand to other models of similar etiology (e.g., acute electroconvulsive seizures, acute chemoconvulsant seizures, chronic electroconvulsive seizures, chronic chemoconvulsant seizures, and spontaneous seizures). Table 1) that are used widely in ASD discovery and can be performed in rats and mice, 6,16,[21][22][23] but other animal species are also susceptible to electrically evoked seizures. 7 The MES test was first used by Merritt and Putnam in 1937 to characterize the response of cats treated with phenytoin 7 ; 1 year later, phenytoin was clinically available, thus validating the MES test.…”

Section: Additional Crfs and Cdesmentioning

confidence: 99%

“…The maximal electroshock test (or MES), maximal electroshock threshold test (MEST), minimal clonic threshold test (MCT), and 6 Hz test all represent frequently used models of electrically evoked acute seizures (Table ) that are used widely in ASD discovery and can be performed in rats and mice, but other animal species are also susceptible to electrically evoked seizures . The MES test was first used by Merritt and Putnam in 1937 to characterize the response of cats treated with phenytoin; 1 year later, phenytoin was clinically available, thus validating the MES test.…”

Section: Example Crfsmentioning

confidence: 99%

A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force

et al. 2018

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SummaryPreclinical pharmacology studies in animal models of seizures and epilepsy have provided a platform to identify more than 20 antiseizure drugs in recent decades. To minimize variability in lab‐to‐lab studies and to harmonize approaches to data collection and reporting methodology in pharmacologic evaluations of the next generation of therapies, we present common data elements (CDEs), case report forms (CRFs), and this companion manuscript to help with the implementation of methods for studies in established preclinical seizure and epilepsy models in adult rodents. The development of and advocacy for CDEs in preclinical research has been encouraged previously by both clinical and preclinical groups. It is anticipated that adoption and implementation of these CDEs in preclinical studies may help standardize approaches to minimize variability and increase the reproducibility of preclinical studies. Moreover, they may provide a methodologic framework for pharmacology studies in atypical animal models or models in development, which may ultimately promote novel therapy development. In the present document, we refer selectively to animal models that have a long history of preclinical use, and in some cases, are clinically validated.

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“…This study was designed to evaluate the systemic and behavioral impact of repeated administration of MC at a concentration (0.5%) most commonly used for early evaluations of investigational drugs for many clinical disorders, including epilepsy, cancer, and neuropathic pain (Ehteda et al, 2012;G et al, 2014;White and Barker-Haliski, 2016;Smith et al, 2017;Patra et al, 2019), and determine whether low-concentration MC itself incites systemic lesions that could affect our ability to adequately assess novel ASDs or other investigational agents. Finally, because epilepsy itself is associated with increased central neuroinflammation (Vezzani et al, 2013;Barker-Haliski et al, 2017b), and peripheral inflammation may also exacerbate seizure severity or accelerate epileptogenesis (Auvin et al, 2010a,b;Cusick et al, 2013), any induction of systemic inflammation may alter the disease pathogenesis in our CKM model, which may further modify the preclinical model phenotype.…”

Section: Introductionmentioning

confidence: 99%

Repeated Intraperitoneal Administration of Low-Concentration Methylcellulose Leads to Systemic Histologic Lesions Without Loss of Preclinical Phenotype

Meeker

Beckman

Knox

et al. 2019

J Pharmacol Exp Ther

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Methylcellulose (MC; 0.5% concentration) is commonly used when evaluating investigational agents for efficacy in preclinical models of disease. When administered by the oral (PO) route, MC is considered a Food and Drug Administration "generally recognized as safe" compound. Yet, there is limited data pertaining to the tolerability and impact on model fidelity of repeated intraperitoneal administration of 0.5% MC. Chronic administration of high-concentration MC (2%-2.5%) has been used to induce anemia, splenomegaly, and lesions in multiple organ systems in several preclinical species. Histopathological findings from a diagnostic pathologic analysis of a single mouse from our laboratory with experimentally induced chronic seizures that had received repeated intraperitoneal administration of antiseizure drugs delivered in MC revealed similar widespread lesions. This study thus tested the hypothesis that chronic administration of intraperitoneal, but not PO, MC incites histologic lesions without effects on preclinical phenotype. Male CF-1 mice (n 5 2-14/group) were randomized to receive either 6 weeks of twice weekly 0.5% MC or saline (intraperitoneal or PO) following induction of chronic seizures.Histology of a subset of mice revealed lesions in kidney, liver, mediastinal lymph nodes, mesentery, aorta, and choroid plexus only in intraperitoneal MC-treated mice (n 5 7/7). Kindled mice that received MC PO (n 5 5) or saline (intraperitoneal n 5 6, PO n 5 3) had no lesions. There were no effects of intraperitoneal MC treatment on body weight, appearance, seizure stability, or behavior. Nonetheless, our findings suggest that repeated intraperitoneal, but not PO, MC elicits systemic organ damage without impacting the model phenotype, which may confound interpretation of investigational drug-induced histologic lesions. SIGNIFICANCE STATEMENTMethylcellulose (0.5% concentration) is commonly used when evaluating investigational agents for efficacy in preclinical models of disease. Herein, we demonstrate that repeated administration of 0.5% methylcellulose by the intraperitoneal, but not oral, route results in systemic inflammation and presence of foam-laden macrophages but does not impact the behavioral phenotype of a rodent model of neurological disease.

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Antiepileptic Drug Discovery

Cited by 6 publications

References 75 publications

Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models

Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models

A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force

Repeated Intraperitoneal Administration of Low-Concentration Methylcellulose Leads to Systemic Histologic Lesions Without Loss of Preclinical Phenotype

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