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Drug‐Induced Neurotoxicity Assessments: Validation of a Neurological and Functional Observation Battery in the Sinclair Miniature Swine
Author(s) -
StrickerKrongrad Alain,
Zhong Miao,
Fuller Amber,
Brocksmith Derek,
Liu Jason,
Bouchard Guy
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1186.5
Subject(s) - neuroscience , medicine , neurotoxicity , central nervous system , motor coordination , amphetamine , safety pharmacology , drug , pharmacology , psychology , toxicity , dopamine
The nervous system is one of the most complex organs in the body, and has its unique vulnerabilities to toxic compounds. The central nervous system, along with cardiovascular and respiratory systems, has been listed in the safety pharmacology core battery of the harmonized test guidelines for preclinical testing of human pharmaceuticals (ICH S7A, 2000). A functional observational battery (FOB) has been recommended in the guideline as the first tier neurotoxicity screening that encompasses motor activity, behavioral changes, coordination, sensor/motor reflex responses, and body temperature. The miniature swine is an appropriate species for neurological and behavioral studies: its central nervous system and specifically the brain are similar to those of human with respect to tissue composition, gyrencephalic structure, and developmental growth and myelination patterns. In addition, behavioral studies, as well as modeling of neurological human diseases, have been increasingly performed in minipigs. Because the miniature swine has increasingly been used as an alternative to dog or non‐human primate in regulatory toxicology studies, we wanted to validate a FOB for the safety pharmacology assessment of pharmaceutical products intended for human use. A swine FOB protocol was developed with multiple observation parameters to monitor effects on six majors categories related to sensory and motor functions, autonomic and voluntary functions and behavior. A crossover study was performed to capture the neurological effects of CNS acting agents administered to the Sinclair minipigs via intramuscular route. Amphetamine, ketamine and diazepam were demonstrated to positively or negatively dose‐dependently affect different parameters related to autonomic functions, excitability, behavior, motor activities, gait and reflexes.Open‐Field Behavioral Observations in Minipig