Neurobehavioral effects of cinnabar and the cinnabar-containing pediatric prescription, Yi-Nian-Jin, in juvenile rats

Cinnabar, a mercury-containing mineral medicine, has long been widely used in pediatric prescriptions. The safety of cinnabar-containing prescriptions, particularly for children, is drawing increasing attention worldwide. However, whether cinnabar and these pediatric prescriptions have adverse effects on neurobehavior is unknown. Yi-Nian-Jin (YNJ), a classic pediatric prescription, contains 5.66% (w/w) cinnabar, along with other four herbs. YNJ is widely prescribed to promote digestion, eliminate phlegm, and prevent constipation in children (aged 0-6 years). In this study, we used YNJ as an example of cinnabar-containing pediatric prescriptions to determine mercury absorption, distribution, and accumulation and further investigate its potential neurotoxicity in juvenile rats.Low (67.9 mg/kg), middle (169.8 mg/kg), and high dose (339.6 mg/kg) of cinnabar, and low (1.2 g/kg), middle (3.0 g/kg), and high dose (6.0 g/kg) of YNJ were used in this study, corresponding to 3, 7.5, and 15 times the clinically equivalent dose, respectively. Juvenile rats were orally administered different doses of cinnabar or YNJ for 14 consecutive days. The mercury content in rat blood and tissues (brain, liver, and kidney) and serum biochemical changes on day 14 of consecutive administration and on day 14 after cessation were measured. Moreover, a series of behavioral assays (open field, elevated plus-maze, and Morris water maze assays) were performed after 14 consecutive days of administration.The mercury absorption, distribution, and accumulation of cinnabar and YNJ in juvenile rats were substantially different. Mercury in cinnabar was absorbed to a greater extent than that in YNJ, and the mercury content in cinnabar high-dose group (cinnabar-H) was approximately seven times higher than that in YNJ high-dose group (YNJ-H) on day 14 of administration. In contrast, compared with that of cinnabar, the mercury content in YNJ accumulated more in the tissues, especially in the brain and kidney. Repeated administration of cinnabar or YNJ did not affect liver function, renal function, learning, and memory in juvenile rats. However, repeated administration of YNJ at a high dose (6.0 g/kg) affected locomotor activity in juvenile rats. Repeated administration of cinnabar (339.6 mg/kg) or YNJ (>1.2 g/kg) induced anxiety-related behavior in juvenile rats.Mercury in YNJ exhibited lower absorption but higher accumulation in tissues than those of the mercury in cinnabar. Consecutive oral administration of cinnabar or YNJ had no impact on liver function, renal function, learning, and memory, but could cause motor dysfunction and anxiety in juvenile rats.