Approaches to seizure risk assessment in preclinical drug discovery

Easter, Alison; Bell, M. Elizabeth; Damewood, James; Redfern, William S.; Valentin, Jean‐Pierre; Winter, Matthew J.; Fonck, Carlos; Bialecki, Russell

doi:10.1016/j.drudis.2009.06.003

Cited by 86 publications

(31 citation statements)

References 48 publications

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“…These data support the potential utility of a slice culture based screening system to discriminate between pharmacological mechanisms underlying changes in NF-κB-regulated stress responsive genes. In comparison to in vivo models, the system described can provide higher throughput detection of changes in IEG expression associated with seizurogenic compounds and offers the added advantage of monitoring multiple concurrent endpoints such as electrophysiological alterations corresponding to changes in gene expression (Easter et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

“…Consequently, seizure liability of new candidate drugs is of primary concern in safety assessment due to its high incidence and the potentially life-threatening consequences of such an adverse drug reaction. Historically, seizure liability has been assessed in late stage preclinical safety assessment during repeated high-dose toxicity studies, with overt behavioral signs of seizure as the only positive indicator of liability (Easter et al, 2009). The inherent limitation of a strictly behavioral method of detection is low sensitivity, where moderate seizurogenic activity may only be indicated by subtle behavioral changes that are difficult to distinguish from generalized stereotypic behavior.…”

Section: Introductionmentioning

confidence: 99%

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Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-κB) prior to seizure in transgenic NF-κB/EGFP reporter mice

et al. 2014

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Predicting seizurogenic properties of pharmacologically active compounds is difficult due to the complex nature of the mechanisms involved and because of the low sensitivity and high variability associated with current behavioral-based methods. To identify early neuronal signaling events predictive of seizure, we exposed transgenic NF-κB/EGFP reporter mice to multiple low doses of kainic acid (KA), postulating that activation of the stress-responsive NF-κB pathway could be a sensitive indicator of seizurogenic potential. The sub-threshold dose level proximal to the induction of seizure was determined as 2.5 mg/Kg KA, using video EEG monitoring. Subsequent analysis of reporter expression demonstrated significant increases in NF-κB activation in the CA3 and CA1 regions of the hippocampus 24 hrs after a single dose of 2.5 mg/Kg KA. This response was primarily observed in pyramidal neurons with little non-neuronal expression. Neuronal NF-κB/EGFP expression was observed in the absence of glial activation, indicating a lack of neurodegeneration-induced neuroinflammation. Protein expression of the immediate-early gene, Nurr1, increased in neurons in parallel to NF-κB activation, supporting that the sub-threshold doses of KA employed directly caused neuronal stress. Lastly, KA also stimulated NF-κB activation in organotypic hippocampal slice cultures established from NF-κB/EGFP reporter mice. Collectively, these data demonstrate the potential advantages of using genetically encoded stress pathway reporter models in the screening of seizurogenic properties of new pharamacologically active compounds.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-κB) prior to seizure in transgenic NF-κB/EGFP reporter mice

et al. 2014

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“…In a recent review it was described that the largest therapy area represented within a group of 275 seizure-associated agents was CNS disorders (35 %). Agents associated with other therapy areas were also well represented, including infection (16 %), cardiovascular (14 %), respiratory (12 %), and metabolism (6 %) (Easter et al 2009). Although marketed drugs can cause seizures in some patients, these seizures generally occur at doses/exposures that are significantly higher than the recommended therapeutic ranges.…”

Section: Seizure Risk Assessmentmentioning

confidence: 98%

“…However, due to the serious potential consequences of druginduced seizures, a number of optional follow-up studies may be used to address this issue, and, depending on the therapy area and patient population being targeted, significant effort is expended in preclinical safety assessment to identify and mitigate seizure risk. Such studies are usually undertaken if there are risk flags that would indicate seizure potential during early discovery, such as (a) existing data suggesting that the compounds from that chemical or drug class are seizurogenic, (b) evidence or knowledge that the compound penetrates the bloodbrain barrier, (c) pharmacological profile indicating that the compound interacts with molecular targets associated with seizure risk, and/or (d) any in vivo behavioral observation suggesting convulsions or other abnormal CNS effects (Easter et al 2009). …”

Section: Seizure Risk Assessmentmentioning

confidence: 99%

CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology

Fonck

Easter

Pietras

et al. 2015

Principles of Safety Pharmacology

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This chapter describes various approaches for the preclinical assessment of drug-induced central nervous system (CNS) adverse effects. Traditionally, methods to evaluate CNS effects have consisted of observing and scoring behavioral responses of animals after drug is administered. Among several behavioral testing paradigms, the Irwin and the functional observational battery (FOB) are the most commonly used assays for the assessment of CNS effects. The Irwin and FOB are considered good first-tier assays to satisfy the ICH S7A guidance for the preclinical evaluation of new chemical entities (NCE) intended for humans. However, experts have expressed concern about the subjectivity and lack of quantitation that is derived from behavioral testing. More importantly, it is difficult to gain insight into potential mechanisms of toxicity by assessing behavioral outcomes. As a complement to behavioral testing, we propose using electrophysiology-based assays, both in vivo and in vitro, such as electroencephalograms and brain slice field-potential recordings. To better illustrate these approaches, we discuss the implementation of electrophysiology-based techniques in drug-induced assessment of seizure risk, sleep disruption, and cognitive impairment.

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“…66 Mn is well described as an agent that causes damage to the CNS, in part, through increases in excitoxicity and altered glutamatergic neurotransmission, 67 and may therefore be a relevant environmental factor affecting the seizurogenic potential of other compounds, which is notoriously difficult to predict. 68 The events that lead to epileptogenesis are only partially defined and a large fraction of individuals with epilepsy are either refractory to current treatments or experience important side effects. 69 Postmortem examination of patients with intractable epilepsy has consistently identified the presence of astrogliosis and microgliosis, 70 stimulating intense research focused on the involvement of glial inflammation in the etiopathogenesis of this disease.…”

Section: Seizurementioning

confidence: 99%

Manganese and Neuroinflammation

Kirkley¹,

Tjalkens²

2014

Manganese in Health and Disease

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Neurotoxicity due to excessive exposure to manganese (Mn) has been described as early as 1837. Despite extensive study over the past century, it is only now becoming clear that Mn neurotoxicity involves complex pathophysiological signaling mechanisms between neurons and glial cells. Glial cells are an important target of Mn in the brain, where high levels of the metal accumulate, activating inflammatory signaling pathways that damage neurons through overproduction of numerous reactive oxygen and nitrogen species and inflammatory cytokines. Understanding how these pathways are regulated in glial cells during Mn exposure is critical to determining the mechanisms underlying permanent neurological dysfunction stemming from excess exposure. Neuroinflammatory activation of glial cells is an important mechanism in Mn neurotoxicity and in other degenerative conditions of the central nervous system. Recent studies have redefined the importance of astrocytes and microglia to neuronal development, homeostasis, and survival, transforming our understanding of the role of these cells from inert structural components to important components of brain physiology and pathology. This chapter will describe the role of microglia and astrocytes in the neurotoxicity of Mn and outline how Mn-dependent neuroinflammatory signaling mechanisms are regulated at a molecular level in these cell types. In addition, methods for studying interactions between glial cell types will also be discussed in context of deciphering which inflammatory signaling molecules are critical to neuronal injury during Mn exposure.

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Approaches to seizure risk assessment in preclinical drug discovery

Cited by 86 publications

References 48 publications

Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-κB) prior to seizure in transgenic NF-κB/EGFP reporter mice

Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-κB) prior to seizure in transgenic NF-κB/EGFP reporter mice

CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology

Manganese and Neuroinflammation

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