Arteether Neurotoxicity in the Absence of Deficits in Behavioural Performance inRats

摘要

The artemesinin-derivative, arteether, is an effective antimalarial agentcurrently under clinical investigation. We evaluated the effects of a chronic daily dose of arteether (12.5 mg/kg/day) using an operant conditioning paradigm. Rats were trained to lever press for food reinforcement under a variable-interval 18 sec schedule of food reinforcement. Arteether (n=6) or oil vehicle (n=6) was administered pre-session for 17 consecutive days. Neither treatment affected the rate or pattern of responding produced by the schedule (i.e., behavior was not disrupted). Subsequent histopathological analysis, however, revealed that arteether, but not vehicle, produced significant neuronal damage in the nucleus trapezoideus (a component of the auditory system) and, to a lesser extent, the nucleus ruber. The nucleus facialis was unaffected in either group. These results extend previous studies investigating arteether neurotoxicity. These results also suggest that auditory dysfunction may provide a sensitive behavioral measure of arteether neurotoxicity.