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Neurobehavioral and Cardiovascular Effects of Potassium Cyanide Administered Orally to Mice
Michael A Hawk1, Glenn D Ritchie1, Kim A Henderson1
1Battelle, Columbus, OH, USA.
Abstract:
The Food and Drug Administration Animal Rule requires evaluation of cardiovascular and central nervous system (CNS) effects of new therapeutics. To characterize an adult and juvenile mouse model, neurobehavioral and cardiovascular effects and pathology of a single sublethal but toxic, 8 mg/kg, oral dose of potassium cyanide (KCN) for up to 41 days postdosing were investigated. This study describes the short- and long-term sensory, motor, cognitive, and behavioral changes associated with oral dosing of a sublethal but toxic dose of KCN utilizing functional observation battery and Tier II CNS testing in adult and juvenile mice of both sexes. Selected tissues (histopathology) were evaluated for changes associated with KCN exposure with special attention to brain regions. Telemetry (adult mice only) was used to evaluate cardiovascular and temperature changes. Neurobehavioral capacity, sensorimotor responsivity or spontaneous locomotor activity, and rectal temperature were significantly reduced in adult and juvenile mice at 30 minutes post-8 mg/kg KCN dose. Immediate effects of cyanide included bradycardia, adverse electrocardiogram arrhythmic events, hypotension, and hypothermia with recovery by approximately 1 hour for blood pressure and heart rate effects and by 2 hours for body temperature. Lesions consistent with hypoxia, such as mild acute tubular necrosis in the kidneys corticomedullary junction, were the only histopathological findings and occurred at a very low incidence. The mouse KCN intoxication model indicates rapid and completely reversible effects in adult and juvenile mice following a single oral 8 mg/kg dose. Neurobehavioral and cardiovascular measurements can be used in this animal model as a trigger for treatment.
Insights
A single oral dose of potassium cyanide (KCN) in mice caused temporary neurobehavioral and cardiovascular changes. These effects were rapid and fully reversible, suggesting KCN mouse models are useful for therapeutic evaluation.
Area of Science:
- Toxicology
- Neuroscience
- Cardiovascular Science
Background:
- The FDA Animal Rule mandates assessment of cardiovascular and central nervous system (CNS) effects for new therapeutics.
- Characterizing animal models is crucial for evaluating therapeutic efficacy and safety.
Purpose of the Study:
- To characterize the neurobehavioral and cardiovascular effects of a sublethal oral dose of potassium cyanide (KCN) in adult and juvenile mice.
- To evaluate the short- and long-term impacts of KCN exposure on sensory, motor, cognitive, and behavioral functions.
- To assess histopathological changes and cardiovascular parameters following KCN intoxication.
Main Methods:
- Oral administration of a single 8 mg/kg dose of KCN to adult and juvenile mice of both sexes.
- Utilized functional observation battery and Tier II CNS testing for neurobehavioral assessments.
- Employed telemetry for cardiovascular and temperature monitoring in adult mice.
- Conducted histopathological examination of selected tissues, with a focus on brain regions.
Main Results:
- Significant reductions in neurobehavioral capacity, sensorimotor responsivity, locomotor activity, and rectal temperature were observed 30 minutes post-KCN dose.
- Immediate cardiovascular effects included bradycardia, arrhythmias, hypotension, and hypothermia, with recovery within 1-2 hours.
- Mild acute tubular necrosis in the kidneys was the sole histopathological finding, occurring at a low incidence.
- All observed effects were rapid and completely reversible within the study period.
Conclusions:
- The mouse model effectively demonstrates rapid and reversible neurobehavioral and cardiovascular effects following a single oral KCN dose.
- This model is suitable for evaluating potential therapeutics targeting cyanide poisoning.
- Neurobehavioral and cardiovascular measurements can serve as critical indicators for initiating treatment in KCN-exposed individuals.
