The Role of Neuropathology Evaluation in the Nonclinical Assessment of Seizure Liability

癫痫 神经科学 海马结构 神经病理学 脑损伤 新皮层 医学 海马硬化 心理学 麻醉 病理 颞叶 疾病
作者
Katie Sokolowski,Judy Liu,Marcus S. Delatte,Simon Authier,Owen McMaster,Brad Bolon
出处
期刊:Toxicologic Pathology [SAGE Publishing]
卷期号:52 (8): 566-573
标识
DOI:10.1177/01926233241300065
摘要

Test article (TA)-induced seizures represent a major safety concern in drug development. Seizures (altered brain wave [electrophysiological] patterns) present clinically as abnormal consciousness with or without tonic/clonic convulsions (where "tonic" = stiffening and "clonic" = involuntary rhythmical movements). Neuropathological findings following seizures may be detected using many methods. Neuro-imaging may show a structural abnormality underlying seizures, such as focal cortical dysplasia or hippocampal sclerosis in patients with chronic epilepsy. Neural cell type-specific biomarkers in blood or cerebrospinal fluid may highlight neuronal damage and/or glial reactions but are not specific indicators of seizures while serum electrolyte and glucose imbalances may induce seizures. Gross observations and brain weights generally are unaffected by TAs with seizurogenic potential, but microscopic evaluation may reveal seizure-related neuron death in some brain regions (especially neocortex, hippocampus, and/or cerebellum). Current globally accepted best practices for neural sampling in nonclinical general toxicity studies provide a suitable screen for brain regions that are known sites of electrical disruption and/or display seizure-induced neural damage. Conventional nonclinical studies can afford an indication that a TA has a potential seizure liability (via in-life signs and/or microscopic evidence of neuron necrosis), but confirmation requires measuring brain electrical (electroencephalographic) activity in a nonclinical study.
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