Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan.
J Neurochem. 2014 Mar;128(5):764-75. doi: 10.1111/jnc.12496. Epub 2013 Dec 3.
Psychostimulant methamphetamine (METH) is toxic to striatal dopaminergic and serotonergic nerve terminals in adult, but not in the adolescent, brain. Betulinic acid (BA) and its derivatives are promising anti-HIV agents with some toxic properties. Many METH users, particularly young men, are HIV-positive; therefore, they might be treated with BA or its derivative for HIV infection. It is not known whether BA, or any of its derivatives, are neurotoxic in combination with METH in the adolescent brain. The present study investigated the effects of BA and binge METH in the striatum of late adolescent rats. BA or METH alone did not decrease the levels of dopaminergic or serotonergic markers in the striatum whereas BA and METH together decreased these markers in a BA dose-dependent manner. BA+METH also caused decreases in the levels of mitochondrial complex I in the same manner; BA alone only slightly decreased the levels of this enzyme in striatal synaptosomes. BA or METH alone increased cytochrome c. METH alone decreased parkin, increased complex II and striatal BA levels. These results suggest that METH in combination with BA can be neurotoxic to striatal dopaminergic and serotonergic nerve terminals in the late adolescent brain via mitochondrial dysfunction and parkin deficit. We report a synergistic neurotoxicity of betulinic acid (BA) and methamphetamine (METH) to monoaminergic terminals in the striatum of male late adolescent rats. BA contribution to the neurotoxicity is decreasing mitochondrial complex I whereas METH contribution is decreasing parkin and increasing brain concentration of BA. We propose that clinical use of BA in young male METH users can be neurotoxic.
苯丙胺类兴奋剂（METH）对成年期纹状体的多巴胺能和 5-羟色胺能神经末梢有毒性，但对青春期大脑没有毒性。白桦脂酸（BA）及其衍生物是有前途的抗 HIV 药物，但具有一些毒性。许多 METH 使用者，特别是年轻男性，HIV 呈阳性；因此，他们可能会因 HIV 感染而接受 BA 或其衍生物的治疗。目前尚不清楚 BA 或其任何衍生物与 METH 联合使用是否会对青春期大脑造成神经毒性。本研究调查了 BA 和狂欢 METH 对青春期后期大鼠纹状体的影响。BA 或 METH 单独使用不会降低纹状体中多巴胺能或 5-羟色胺能标志物的水平，而 BA 和 METH 联合使用会以 BA 剂量依赖的方式降低这些标志物的水平。BA+METH 也以同样的方式导致线粒体复合物 I 水平降低；BA 单独使用仅会轻微降低纹状体突触体中这种酶的水平。BA 或 METH 单独使用会增加细胞色素 c。METH 单独使用会降低 parkin 水平，增加复合物 II 和纹状体 BA 水平。这些结果表明，METH 与 BA 联合使用可通过线粒体功能障碍和 parkin 缺乏导致青春期后期大脑纹状体多巴胺能和 5-羟色胺能神经末梢的神经毒性。我们报告了 BA 和 METH 对雄性青春期后期大鼠纹状体单胺能末梢的协同神经毒性。BA 的神经毒性作用是降低线粒体复合物 I，而 METH 的神经毒性作用是降低 parkin 并增加脑内 BA 浓度。我们提出，在年轻男性 METH 使用者中临床使用 BA 可能具有神经毒性。
