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Development of a Functional Observational Battery in the Minipig for Regulatory Neurotoxicity Assessments
Miao Zhong1, Catherine Shoemake1, Amber Fuller1
11 Sinclair Research Center, LLC, Auxvasse, MO, USA.
Abstract:
A functional observational battery (FOB) is recommended as the first-tier neurotoxicity screening in the preclinical safety pharmacology testing guidelines. Minipigs have increasingly been used in regulatory toxicology studies; however, no current FOB protocol is available for neurotoxicity testing in these species. Hence, a minipig FOB instrument was developed. A complete crossover study with Sinclair minipigs was performed to evaluate physiologic, neurologic, and behavioral effects of amphetamine, ketamine, and diazepam. The treated minipigs were first observed in their home cage, were video-recorded for 10 minutes in an open field, and then went through a complete neurologic examination. Both ketamine and diazepam were shown to reduce the freezing and behavior shifts of treated minipigs, while increasing their exploratory behaviors. Both drugs also caused muscular and gait impairment. The effects of ketamine and diazepam were consistent with their roles as central nervous system (CNS) suppressants. Unique effects were also observed with ketamine and diazepam treatments, which may reflect their unique mechanisms of action. Consistent with its role as a CNS stimulant, amphetamine caused the treated minipigs to be hyperactive and to display increased freezing and behavior shifts and reduced exploring activities. These effects of amphetamine were opposite to those observed with ketamine and diazepam. Amphetamine also increased locomotion in the treated minipigs. The present effects of amphetamine, ketamine, and diazepam are in agreement with observations by others. In conclusion, the minipig is a suitable species for FOB evaluation of pharmaceuticals in preclinical safety pharmacology testing.
Insights
A new functional observational battery (FOB) for minipigs enables neurotoxicity screening. This preclinical safety test accurately identified CNS stimulant and suppressant drug effects, validating the minipig as a suitable model.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Functional observational battery (FOB) is a key preclinical neurotoxicity screening tool.
- Minipigs are increasingly used in toxicology, but lack a standardized FOB protocol for neurotoxicity assessment.
Purpose of the Study:
- Develop and validate a minipig FOB protocol for preclinical neurotoxicity testing.
- Evaluate the effects of CNS stimulant (amphetamine) and suppressant (ketamine, diazepam) drugs in minipigs using the developed FOB.
Main Methods:
- A crossover study design was employed with Sinclair minipigs.
- Minipigs underwent home cage observation, open-field video recording, and a full neurologic examination.
- Physiologic, neurologic, and behavioral effects of amphetamine, ketamine, and diazepam were assessed.
Main Results:
- Ketamine and diazepam (CNS suppressants) decreased freezing, reduced behavior shifts, and increased exploratory behaviors, alongside muscle and gait impairment.
- Amphetamine (CNS stimulant) induced hyperactivity, increased freezing, behavior shifts, reduced exploration, and increased locomotion.
- Observed drug effects align with known pharmacological actions and support the minipig's suitability for FOB.
Conclusions:
- The developed minipig FOB is effective for evaluating drug-induced neurotoxicity.
- Minipigs demonstrate differential behavioral and neurologic responses to CNS stimulants and suppressants.
- This protocol supports the minipig as a valuable species for preclinical safety pharmacology testing.
