Behavioral and neural toxicity of the artemisinin antimalarial, arteether,but not artesunate and artelinate, in rats

Three artemisinin antimalarials, arteether (AE), artesunate (AS), and artel inate (AL) were evaluated in rats using an auditory discrimination task (AD T) and neurohistology. After rats were trained on the ADT, equimolar doses of AE (25 mg/kg, in sesame oil, n = 6), AS (31 mg/kg, in sodium carbonate, n = 6), and AL (36 mg/kg, in saline, n = 6), or vehicle (sodium carbonate, n = 6) were administered (WI) for 7 consecutive days. Behavioral performanc e was evaluated, during daily sessions, before, during, and after administr ation. Histological evaluation of the brains was performed using thionine s taining, and damaged cells were counted in specific brainstem nuclei of all rats. Behavioral performance was not significantly affected in any rats tr eated with AS, AL, or vehicle. Furthermore, histological examination of the brains of rats treated with AS, AL, and vehicle did not show damage. In st ark contrast, all rats treated with AE showed a progressive and severe decl ine in performance on the ADT. The deficit was characterized by decreases i n accuracy, increases in response time and, eventually, response suppressio n. When performance on the ADT was suppressed, rats also showed gross behav ioral signs of toxicity that included tremor, gait disturbances, and lethar gy. Subsequent histological assessment of AE-treated rats revealed marked d amage in the brainstem nuclei, ruber, superior olive, trapezoideus, and inf erior vestibular. The damage included chromatolysis, necrosis, and gliosis. These results demonstrate distinct differences in the ability of artemisin ins to produce neurotoxicity. Further research is needed to uncover pharmac okinetic and metabolic differences in artemisinins that may predict neuroto xic potential. (C) 2000 Elsevier Science Inc. All rights reserved.