Toovey Stephen, Bustamante Leyla Y, Uhlemann Anne-Catrin, East J Malcolm, Krishna Sanjeev
Academic Centre for Travel Medicine & Vaccines, WHO Collaborating Centre for Travel Medicine, Royal Free & University College Medical School, London, UK.
Basic Clin Pharmacol Toxicol. 2008 Sep;103(3):209-13. doi: 10.1111/j.1742-7843.2008.00256.x. Epub 2008 Jul 18.
The aim of this study was to assess the ability of currently deployed antimalarials to inhibit mammalian sarcoendoplasmic reticulum calcium adenosine triphosphatase (SERCA). Artemisinins exert their antiplasmodial action by inhibiting parasite PfATP6, a SERCA enzyme, and possess neurotoxic potential; mefloquine is neurotoxic and inhibits mammalian SERCA, an orthologue of PfATP6. SERCA in rabbit muscle was tested in vitro for inhibition by artemisinin and amino alcohol antimalarials. Significant inhibition of mammalian SERCA, as mean difference from uninhibited, control values was seen with both enantiomers of mefloquine: (+)-mefloquine (10 microM: -35.83, 95% CI -59.63 to -12.03; 50 microM: -54.06, 95% CI -77.86 to -30.26); (-)-mefloquine (10 microM: -24.35, 95% CI -41.56 to -7.15; 50 microM: -58.42, 95% CI -75.62 to -41.22); lumefantrine (1 microM: -25.46, 95% CI -45.82 to -5.10; 5 microM -34.83, 95% CI -60.08 to -9.58; 10 microM: -25.80, 95% CI -51.05 to -0.55); desbutyl-lumefantrine (5 microM: -50.16, 95% CI -84.24 to -16.08); dihydroartemisinin (1 microM: -39.25, 95% CI -63.74 to -14.76; 5 microM: -39.30, 95% CI -64.88 to -13.72). Dihydroartemisinin in higher concentrations (10 microM) stimulated SERCA activity: (+40.90, 95% CI 11.37 to 70.44). No statistically significant inhibition was seen with artemether at 1, 5 and 10 microM. Equimolar combinations of artemether and lumefantrine or of dihydroartemisinin and lumefantrine, when studied at concentrations that inhibit SERCA individually, failed to show any inhibition. Dihydroartemisinin, mefloquine, lumefantrine and desbutyl lumefantrine inhibit mammalian SERCA at periphysiological concentrations, although the neurotoxicity of mefloquine is not wholly attributable to this property. Candidate antimalarials should be screened pre-clinically for SERCA inhibition.
本研究的目的是评估当前使用的抗疟药抑制哺乳动物肌浆网钙三磷酸腺苷酶（SERCA）的能力。青蒿素通过抑制寄生虫PfATP6（一种SERCA酶）发挥其抗疟作用，并具有神经毒性潜力；甲氟喹具有神经毒性，可抑制哺乳动物的SERCA（PfATP6的同源物）。在体外测试了青蒿素和氨基醇类抗疟药对兔肌肉中SERCA的抑制作用。甲氟喹的两种对映体均对哺乳动物SERCA产生了显著抑制，与未受抑制的对照值相比的平均差异如下：（+）-甲氟喹（10微摩尔：-35.83，95%置信区间-59.63至-12.03；50微摩尔：-54.06，95%置信区间-77.86至-30.26）；（-）-甲氟喹（10微摩尔：-24.35，95%置信区间-41.56至-7.15；50微摩尔：-58.42，95%置信区间-75.62至-41.22）；本芴醇（1微摩尔：-25.46，95%置信区间-45.82至-5.10；5微摩尔-34.83，95%置信区间-60.08至-9.58；10微摩尔：-25.80，95%置信区间-51.05至-0.55）；去丁基本芴醇（5微摩尔：-50.16，95%置信区间-84.24至-16.08）；双氢青蒿素（1微摩尔：-39.25，95%置信区间-63.74至-14.76；5微摩尔：-39.30，95%置信区间-64.88至-13.72）。较高浓度（10微摩尔）的双氢青蒿素刺激了SERCA活性：（+40.90，95%置信区间11.37至70.44）。蒿甲醚在1、5和10微摩尔时未观察到统计学上显著的抑制作用。当分别以抑制SERCA的浓度研究蒿甲醚与本芴醇或双氢青蒿素与本芴醇的等摩尔组合时，未显示出任何抑制作用。双氢青蒿素、甲氟喹、本芴醇和去丁基本芴醇在生理周边浓度下抑制哺乳动物SERCA，尽管甲氟喹的神经毒性并非完全归因于此特性。候选抗疟药应在临床前进行SERCA抑制筛选。
