Kamchonwongpaisan S, McKeever P, Hossler P, Ziffer H, Meshnick S R
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, USA.
Am J Trop Med Hyg. 1997 Jan;56(1):7-12. doi: 10.4269/ajtmh.1997.56.7.
Despite the wide use of artermisinin and its derivatives, concerns have been raised about their potential neurotoxicity. Accordingly, studies were undertaken on rats treated with high doses of arteether and on mouse neuroblastoma cells (Neu2a) treated with 3H-dihydroartemisinin. Rats uniformly developed neurologic symptoms following intramuscular administration of 50 mg/kg/day of arteether for 5-6 days. Acute neuronal necrosis associated with vacuolization and focal axonal swelling in the neuropil was observed in specific areas of the brain, especially the vestibular nuclei and red nuclei. Scattered swollen neurons were also evident in the cerebellar nuclei and the reticular formation. No neurologic symptoms, neuronal nuclei necrosis, nor gliosis was observed in rats administered 25 or 30 mg/kg/day for six or eight days. In vitro, Neu2a cells took up much less 3H-dihydroartemisinin than Plasmodium falciparum-infected red blood cells when incubated under identical conditions for 4 hr with 4.2 microM 3H-dihydroartemisinin. This selective uptake may explain why the artemisinin derivatives are selectively toxic to malaria parasites. Autoradiograms of sodium dodecyl sulfate-polyacrylamide gels run from 3H-dihydroartemisinin-treated cells showed that neuronal proteins with molecular weights of 27, 32, 40, and 81 kD were alkylated, although not nearly as strongly or rapidly as the P. falciparum proteins. The results indicate that while artemisinin derivatives have neurotoxic effects in rats and alkylate proteins in neuroblastoma cells, these effects only occur at high doses or after prolonged exposure.
尽管青蒿素及其衍生物被广泛使用，但人们对其潜在的神经毒性表示担忧。因此，对用高剂量蒿乙醚处理的大鼠以及用³H - 二氢青蒿素处理的小鼠神经母细胞瘤细胞（Neu2a）进行了研究。大鼠肌肉注射50毫克/千克/天的蒿乙醚，持续5 - 6天，均出现了神经症状。在大脑的特定区域，尤其是前庭核和红核，观察到了与空泡化和神经毡中局灶性轴突肿胀相关的急性神经元坏死。小脑核和网状结构中也可见散在的肿胀神经元。给予25或30毫克/千克/天，持续6或8天的大鼠未观察到神经症状、神经元核坏死或胶质细胞增生。在体外，当在相同条件下用4.2微摩尔³H - 二氢青蒿素孵育4小时时，Neu2a细胞摄取的³H - 二氢青蒿素比恶性疟原虫感染的红细胞少得多。这种选择性摄取可能解释了青蒿素衍生物为何对疟原虫具有选择性毒性。用³H - 二氢青蒿素处理的细胞进行十二烷基硫酸钠 - 聚丙烯酰胺凝胶电泳后的放射自显影片显示，分子量为27、32、40和81千道尔顿的神经元蛋白被烷基化，尽管其程度和速度远不及恶性疟原虫蛋白。结果表明，虽然青蒿素衍生物在大鼠中具有神经毒性作用，并能使神经母细胞瘤细胞中的蛋白烷基化，但这些作用仅在高剂量或长期暴露后才会出现。
