Centre for Biomolecular Interactions Bremen, University of Bremen, PO. Box 330440, 28334, Bremen, Germany.
Neurochem Res. 2013 Dec;38(12):2524-34. doi: 10.1007/s11064-013-1165-2. Epub 2013 Oct 4.
In active antiretroviral therapy antiretroviral drugs are employed for the restoration of a functional immune system in patients suffering from the acquired immunodeficiency syndrome. However, potential adverse effects of such compounds to brain cells are discussed in connection with the development of neurocognitive impairments in patients. To investigate potential effects of antiretroviral drugs on cell viability and the glycolytic flux of brain cells, astrocyte-rich primary cultures were exposed to various antiretroviral compounds, including the non-nucleoside reverse transcriptase inhibitor efavirenz. In a concentration of 10 μM, neither efavirenz nor any of the other investigated antiretroviral compounds acutely compromised the cell viability nor altered glucose consumption or lactate production. In contrast, the primary metabolite of efavirenz, 8-hydroxy-efavirenz, stimulated the glycolytic flux in viable astrocytes in a time- and concentration-dependent manner with half-maximal and maximal effects at concentrations of 5 and 10 μM, respectively. The stimulation of glycolytic flux by 8-hydroxy-efavirenz was not additive to that obtained for astrocytes that were treated with the respiratory chain inhibitor rotenone and was abolished by removal of extracellular 8-hydroxy-efavirenz. In a concentration of 10 μM, 8-hydroxy-efavirenz and efavirenz did not affect mitochondrial respiration, while both compounds lowered in a concentration of 60 μM significantly the oxygen consumption by mitochondria that had been isolated form cultured astrocytes, suggesting that the stimulation of glycolytic flux by 8-hydroxy-efavrienz is not caused by direct inhibition of respiration. The observed alteration of astrocytic glucose metabolism by 8-hydroxy-efavirenz could contribute to the adverse neurological side effects reported for patients that are chronically treated with efavirenz-containing medications.
在抗逆转录病毒疗法中，使用抗逆转录病毒药物来恢复患有获得性免疫缺陷综合征的患者的功能性免疫系统。然而，人们讨论了这些化合物对脑细胞的潜在不良反应，因为这些不良反应与患者神经认知障碍的发展有关。为了研究抗逆转录病毒药物对脑细胞活力和糖酵解通量的潜在影响，用各种抗逆转录病毒化合物（包括非核苷类逆转录酶抑制剂依非韦伦）处理富含星形胶质细胞的原代培养物。在 10μM 的浓度下，依非韦伦和其他研究的抗逆转录病毒化合物都没有急性降低细胞活力，也没有改变葡萄糖消耗或乳酸产生。相反，依非韦伦的主要代谢物 8-羟基依非韦伦以时间和浓度依赖的方式刺激存活星形胶质细胞的糖酵解通量，半最大和最大效应分别在浓度为 5 和 10μM 时达到。8-羟基依非韦伦对呼吸链抑制剂鱼藤酮处理的星形胶质细胞的糖酵解通量的刺激不是加性的，并且通过去除细胞外 8-羟基依非韦伦而被消除。在 10μM 的浓度下，8-羟基依非韦伦和依非韦伦都不影响线粒体呼吸，而这两种化合物在 60μM 的浓度下均显著降低了从培养的星形胶质细胞中分离的线粒体的耗氧量，这表明 8-羟基依非韦伦对糖酵解通量的刺激不是由呼吸的直接抑制引起的。8-羟基依非韦伦对星形胶质细胞葡萄糖代谢的观察到的改变可能导致接受含有依非韦伦的药物进行慢性治疗的患者报告的不良神经副作用。
