Behavioral and neural toxicity of arteether in rats

被引:33
作者
Genovese, RF [1 ]
Newman, DB
Petras, JM
Brewer, TG
机构
[1] Walter Reed Army Med Ctr, Div Neurosci, Washington, DC 20307 USA
[2] Walter Reed Army Med Ctr, Div Expt Therapeut, Washington, DC 20307 USA
[3] Uniformed Serv Univ Hlth Sci, Dept Anat & Cell Biol, Bethesda, MD 20814 USA
关键词
antimalarial; artemisinin; audition; discrimination; neuropathology; safety assessment;
D O I
10.1016/S0091-3057(98)00019-7
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
Repeated administration of the artemisinin antimalarial compound, beta-arteether (AE) (25 mg/kg, IM) was evaluated in rats using a two-choice, discrete trial, auditory discrimination task and subsequent neurohistology. Rats were trained to choose one of two response levers following presentation of white noise or a tone + white noise. Increasing and decreasing the intensity of the tone increased and decreased discriminability, respectively, and differential reinforcement density produced systematic changes in response bias. AE (n = 5) or vehicle (n = 5) was injected daily (9-12 days). Initial injections of AE did not affect behavioral performance. Continuing daily injections produced significant 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, AE was injected for 3 (n = 5), 5 (n = 5), or 7 (n = 5), consecutive days and performance was examined for an additional 7 days. Behavioral disruption was only observed in rats receiving AE for 7 days and the greatest 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 receiving the 3-day regimen. Thus, behavioral disruption reflected, but did not predict, neuropathology. These results confirm and extend earlier results demonstrating neurotoxicity of AE in rats. Further, these results demonstrate that the auditory discrimination task provides an objective behavioral measure of AE neurotoxicity, and thus, can serve as a valuable tool for the safety development of AE and other artemisinin antimalarial compounds. (C) 1998 Elsevier Science Inc.
引用
收藏
页码:449 / 458
页数:10
相关论文
共 27 条
[1]   NEUROTOXICITY IN ANIMALS DUE TO ARTEETHER AND ARTEMETHER [J].
BREWER, TG ;
PEGGINS, JO ;
GRATE, SJ ;
PETRAS, JM ;
LEVINE, BS ;
WEINA, PJ ;
SWEARENGEN, J ;
HEIFFER, MH ;
SCHUSTER, BG .
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 1994, 88 :33-36
[2]   FATAL NEUROTOXICITY OF ARTEETHER AND ARTEMETHER [J].
BREWER, TG ;
GRATE, SJ ;
PEGGINS, JO ;
WEINA, PJ ;
PETRAS, JM ;
LEVINE, BS ;
HEIFFER, MH ;
SCHUSTER, BG .
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 1994, 51 (03) :251-259
[3]  
Buser Pierre A., 1992, Audition
[4]  
CAMMERMEYER J, 1962, Ergeb Anat Entwicklungsgesch, V36, P1
[5]  
CAMMERMEYER JAN, 1961, ACTA NEUROPATHOL, V1, P245
[6]  
China Cooperative Research Group on Qinghaosu and its Derivatives as Antimalarials, 1982, J TRADIT CHIN MED, V2, P31
[7]   ROLE OF ARTEETHER IN THE TREATMENT OF MALARIA AND PLANS FOR FURTHER DEVELOPMENT [J].
DAVIDSON, DE .
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 1994, 88 :51-52
[8]  
DYKSTRA LA, 1987, EXPT PSYCHOPHARMACOL, P393
[9]   ARTEETHER NEUROTOXICITY IN THE ABSENCE OF DEFICITS IN BEHAVIORAL PERFORMANCE IN RATS [J].
GENOVESE, RF ;
PETRAS, JM ;
BREWER, TG .
ANNALS OF TROPICAL MEDICINE AND PARASITOLOGY, 1995, 89 (04) :447-449
[10]  
GENOVESE RF, UNPUB DOSE DEPENDENT