BEHAVIORAL AND NEURAL TOXICITY OF ARTEETHER IN RATS

Repeated administration of the artemisinin antimalarial compound, beta -arteether (AE) (25 mg/kg, IM) was evaluated in rats using a two-choic e, discrete trial, auditory discrimination task and subsequent neurohi stology. Rats were trained to choose one of two response levers follow ing presentation of white noise or a tone + white noise. Increasing an d decreasing the intensity of the tone increased and decreased discrim inability, respectively, and differential reinforcement density produc ed systematic changes in response bias. AE (n = 5) or vehicle (n = 5) was injected daily (9-12 days). Initial injections of AE did not affec t behavioral performance. Continuing daily injections produced signifi cant decreases in choice accuracy and significant increases in choice reaction time. When overt signs of severe toxicity were observed, rats were sacrificed and significant neural pathology was observed in the nucleus trapezoideus of AE-treated rats. In a subsequent experiment, A E was injected for 3 (n = 5), 5 (n = 5), or 7 (n = 5), consecutive day s and performance was examined for an additional 7 days. Behavioral di sruption was only observed in rats receiving AE for 7 days and the gre atest degree of disruption occurred after AE injections were completed . Histopathological examination showed significant neural pathology in the nuclei trapezoideus, superior olive, and ruber of rats receiving 7- and 5-day AE regimens, and in the nucleus trapezoideus of rats rece iving the 3-day regimen. Thus, behavioral disruption reflected, but di d not predict, neuropathology. These results confirm and extend earlie r results demonstrating neurotoxicity of AE in rats. Further, these re sults demonstrate that the auditory discrimination task provides an ob jective behavioral measure of AE neurotoxicity, and thus, can serve as a valuable tool for the safety development of AE and other artemisini n antimalarial compounds. (C) 1998 Elsevier Science Inc.