Neurobehavioral and Cardiovascular Effects of Potassium Cyanide Administered Orally to Mice

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.

Circulatory Failure During Noninhaled Forms of Cyanide Intoxication

“…The experimental approaches we used produced effects that are extremely close to those produced by an acute CN intoxication by ingestion (10, 11). These forms of poisoning are regarded as a potential source of intoxication during a criminal act or a potential terrorist attack.…”

“…These forms of poisoning are regarded as a potential source of intoxication during a criminal act or a potential terrorist attack. Recent studies in rodents (10, 11) have established how rapidly lethal can oral intoxication be (within minutes). These effects are very well mimicked by an IP injection since during both oral or IP administration, the diffusion of CN into the blood does not depend on the level of breathing and CN will continue to diffuse at the same rate regardless of the levels of minute ventilation.…”

“…We used a systemic administration of CN, wherein CN rapidly diffuses to the blood stream, irrespective of the level of pulmonary ventilation as during CN ingestion (10, 11). These intoxications differ from those produced by the inhalation of CN during as CN diffusion into the blood does not increase during the period of hyperventilation or decrease during the period of CN-induced apnea.…”

K252a Prevents Microglial Activation Induced by Anoxic Stimulation of Carotid Bodies in Rats

“…The animals were sacrificed 48 h after the NaCN stimulus to ensure microglial reactivity. This model has been previously proven to induce cyanide toxicity by binding to the mitochondria, blocking electron transport, and inhibiting respiration [54], so it can cause severe CNS depression and death [55]. Our group has previously used this model to analyze c-fos activity and GluR2/3 receptor expression [56,57].…”

Effects of Widely Used Heavy Metals on Embryological Development of Model Organism Zebrafish (Danio rerio)

“…KCN affects organ systems with the highest demand for energy such as the central nervous, cardiovascular, and pulmonary systems (Hawk et al 2016).…”