Stress convulsions in rodents: within a weight-of-evidence framework for human seizure risk
In research settings, rodents exhibit a well-documented sensitivity to stress-induced behavioral alterations ranging from stereotypy to convulsions. These events complicate preclinical drug safety assessments where establishing a No-Observed-Effect Level (NOEL) requires distinguishing true pharmacol...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Toxicology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/ftox.2025.1600816/full |
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| author | Joseph J. DeGeorge Monica R. Metea Monica R. Metea |
| author_facet | Joseph J. DeGeorge Monica R. Metea Monica R. Metea |
| author_sort | Joseph J. DeGeorge |
| collection | DOAJ |
| description | In research settings, rodents exhibit a well-documented sensitivity to stress-induced behavioral alterations ranging from stereotypy to convulsions. These events complicate preclinical drug safety assessments where establishing a No-Observed-Effect Level (NOEL) requires distinguishing true pharmacologic seizures from stress-related convulsions, including a type lacking electrographic cortical correlates, referred to as psychogenic nonepileptic seizures (PNES). Stress triggers in preclinical settings include environmental factors and systemic conditioning effects of investigational drugs unrelated to seizure risk. Stress-induced behaviors can bias safety assessments by creating false-positive findings of seizure liability incorrectly attributed to the test compound. This paper highlights situations when stress conditioning is present during rodent seizure liability studies and proposes a Weight-of-Evidence (WoE) approach to differentiate between drug-induced ES and stress-conditioned PNES. It supports applying context-specific criteria for regulatory considerations especially when convulsions are absent in higher species, when there are inconsistent findings across facilities, and when rodents present stereotypy and lack of neuropathological evidence of drug-induced seizures. This approach aims to minimize the misinterpretation of stress-related artifacts as true pharmacologic seizures, providing a framework for more reliable and translatable seizure liability assessments. |
| format | Article |
| id | doaj-art-e08dabe1ffeb4ac79b6d5c4ecd244b93 |
| institution | DOAJ |
| issn | 2673-3080 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Toxicology |
| spelling | doaj-art-e08dabe1ffeb4ac79b6d5c4ecd244b932025-08-20T03:11:58ZengFrontiers Media S.A.Frontiers in Toxicology2673-30802025-07-01710.3389/ftox.2025.16008161600816Stress convulsions in rodents: within a weight-of-evidence framework for human seizure riskJoseph J. DeGeorge0Monica R. Metea1Monica R. Metea2Bianca Holdings, LLC, Waymart, PA, United StatesPreclinical Electrophysiology Consulting, LLC, Boston, MA, United StatesLucerum, Inc, Boston, MA, United StatesIn research settings, rodents exhibit a well-documented sensitivity to stress-induced behavioral alterations ranging from stereotypy to convulsions. These events complicate preclinical drug safety assessments where establishing a No-Observed-Effect Level (NOEL) requires distinguishing true pharmacologic seizures from stress-related convulsions, including a type lacking electrographic cortical correlates, referred to as psychogenic nonepileptic seizures (PNES). Stress triggers in preclinical settings include environmental factors and systemic conditioning effects of investigational drugs unrelated to seizure risk. Stress-induced behaviors can bias safety assessments by creating false-positive findings of seizure liability incorrectly attributed to the test compound. This paper highlights situations when stress conditioning is present during rodent seizure liability studies and proposes a Weight-of-Evidence (WoE) approach to differentiate between drug-induced ES and stress-conditioned PNES. It supports applying context-specific criteria for regulatory considerations especially when convulsions are absent in higher species, when there are inconsistent findings across facilities, and when rodents present stereotypy and lack of neuropathological evidence of drug-induced seizures. This approach aims to minimize the misinterpretation of stress-related artifacts as true pharmacologic seizures, providing a framework for more reliable and translatable seizure liability assessments.https://www.frontiersin.org/articles/10.3389/ftox.2025.1600816/fullstress-induced convulsionspsychogenic nonepileptic seizures (PNES)electrographic seizures (ES)rodent models in regulatory toxicologypreclinical seizure liability assessmentweight-of-evidence (WoE) framework |
| spellingShingle | Joseph J. DeGeorge Monica R. Metea Monica R. Metea Stress convulsions in rodents: within a weight-of-evidence framework for human seizure risk Frontiers in Toxicology stress-induced convulsions psychogenic nonepileptic seizures (PNES) electrographic seizures (ES) rodent models in regulatory toxicology preclinical seizure liability assessment weight-of-evidence (WoE) framework |
| title | Stress convulsions in rodents: within a weight-of-evidence framework for human seizure risk |
| title_full | Stress convulsions in rodents: within a weight-of-evidence framework for human seizure risk |
| title_fullStr | Stress convulsions in rodents: within a weight-of-evidence framework for human seizure risk |
| title_full_unstemmed | Stress convulsions in rodents: within a weight-of-evidence framework for human seizure risk |
| title_short | Stress convulsions in rodents: within a weight-of-evidence framework for human seizure risk |
| title_sort | stress convulsions in rodents within a weight of evidence framework for human seizure risk |
| topic | stress-induced convulsions psychogenic nonepileptic seizures (PNES) electrographic seizures (ES) rodent models in regulatory toxicology preclinical seizure liability assessment weight-of-evidence (WoE) framework |
| url | https://www.frontiersin.org/articles/10.3389/ftox.2025.1600816/full |
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