Acute high dose arteether toxicity in rats

Acute high dose administration of the artemisinin antimalarial, beta-arteet her (AE), was evaluated in rats using an auditory discrimination task (ADT) and histology. After rats were trained on the ADT, AE (25, 75, 125 mg/kg, IM) or vehicle (sesame oil) was administered and behavioral performance was evaluated for 11 consecutive days. Histological evaluation of the brains w as performed using thionine and cupric-silver staining. Damaged cells were counted in specific brainstem nuclei of all rats and a qualitative analysis of the rostral-caudal extent of selected brains was performed. Behavioral performance was not significantly affected by any treatment although some e vidence of disruption was observed, particularly after the largest dose. Ar 125 mg/kg, AE produced statistically significant neuropathology, including chromatolysis, in the nucleus trapezoideus and nucleus superior olive. AE at 75 mg/kg, produced significant neuropathology in the nucleus trapezoideu s. Neither AE at 25 mg/kg, nor vehicle produced damage. Qualitative analysi s revealed a pattern of neuropathology focused in the brainstem. The result s show that, in rats, a single dose of AE can produce a pattern of brainste m neuropathology and that specific brainstem nuclei, including auditory nuc lei, are particularly vulnerable. These results are consistent with, and ex tend, previous studies demonstrating brainstem neurotoxicity from repeated AE administration. Moreover, early detection of AE-induced neuropathology i s problematic and may require selective examination of brainstem functions. (C) 1999 Inter Press, Inc.