Li Ren-Shi, Takeda Tomoki, Ohshima Takashi, Yamada Hideyuki, Ishii Yuji
Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Green Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Drug Metab Pharmacokinet. 2017 Feb;32(1):108-111. doi: 10.1016/j.dmpk.2016.10.410. Epub 2016 Oct 27.
The chronic neurotoxicity of heroin on the nervous system is poorly understood. To address this issue, we comprehensively assessed the alteration of brain metabolomics caused by chronic heroin exposure and the withdrawal of heroin. Male C57BL/6J mice (n = 10) were given heroin (15 μmol/kg, i.p., twice a day) for 12 days while the withdrawal group received saline-treatment instead of heroin for the last two days. The control group received saline. We developed an UPLC-TOF/MS-based metabolomic approach to analyze the metabolites and carry out a metabolic pathway analysis in the brain. The major metabolites contributing to the discrimination were identified as amino acids, tricarboxylic-acid cycle intermediates, neurotransmitters, nucleotides and other compounds. A marked reduction in histidine and a slight but significant increase in phenylalanine and tryptophan were observed after heroin was withdrawn while the increased level of catecholamines was restored to baseline. Interestingly, N-acetylserotonin - a precursor of melatonin - was increased with the withdrawal of heroin while melatonin was markedly reduced along with the sub-chronic exposure to heroin. This shows that heroin disrupts not only the energy metabolism but also the biosynthesis of both catecholamines and melatonin in the mouse brain. Therefore, these substances are candidate biomarkers for chronic heroin-abuse.
海洛因对神经系统的慢性神经毒性尚不清楚。为了解决这个问题，我们全面评估了慢性海洛因暴露和海洛因戒断引起的脑代谢组学变化。雄性C57BL/6J小鼠（n = 10）每天腹腔注射海洛因（15 μmol/kg，一天两次），持续12天，而戒断组在最后两天接受生理盐水治疗而非海洛因。对照组接受生理盐水。我们开发了一种基于超高效液相色谱-飞行时间质谱的代谢组学方法来分析代谢物，并在脑中进行代谢途径分析。导致差异的主要代谢物被鉴定为氨基酸、三羧酸循环中间体、神经递质、核苷酸和其他化合物。戒断海洛因后，组氨酸显著减少，苯丙氨酸和色氨酸略有但显著增加，而儿茶酚胺水平升高恢复到基线。有趣的是，褪黑素的前体N-乙酰血清素随着海洛因戒断而增加，而褪黑素随着亚慢性海洛因暴露而显著减少。这表明海洛因不仅破坏了小鼠脑中的能量代谢，还破坏了儿茶酚胺和褪黑素的生物合成。因此，这些物质是慢性海洛因滥用的候选生物标志物。
