Xu Boyang, Yan Jun, Zhou Yangtao, Zhang Feng, Wang Binjie, Wang Jiye, Wu Yuanzhao, Xu Yu
Zhejiang Key Laboratory of Drug Prevention and Control Technology, National Narcotics Laboratory Zhejiang Regional Center, Hangzhou, China.
Zhejiang Key Laboratory of Drug Prevention and Control Technology, Department of Criminal Science and Technology, Zhejiang Police College, Hangzhou, China.
J Appl Toxicol. 2025 Mar;45(3):440-451. doi: 10.1002/jat.4715. Epub 2024 Oct 30.
As global regulations on synthetic cannabinoids tighten, illicit vendors increasingly turn to new structures of synthetic cannabinoids to evade legal scrutiny. MDA-19, a novel synthetic cannabinoid, exhibited significant agonistic effects on type 2 cannabinoid receptors in vivo and showed emerging trends of abuse in illicit markets. However, research on the toxicological effects of MDA-19 remains scarce. In this study, we examined the effects of MDA-19 on neurodevelopment, behavior, oxidative stress, and metabolomics by exposing zebrafish embryos to MDA-19 solutions with concentrations of 1, 10, and 20 mg/L over 5 days. Results revealed that exposure to 10 and 20 mg/L of MDA-19 accelerated hatching in zebrafish embryos but led to reduced body length without affecting mortality or malformation. Furthermore, exposure to all concentrations of MDA-19 resulted in diminished swimming ability and reduced activity time in zebrafish. Transgenic zebrafish (hb9-GFP) exposed to MDA-19 exhibited impaired development of spinal motor neurons. Notably, exposure to 20 mg/L MDA-19 increased the levels of reactive oxygen species (ROS) in zebrafish and elevated the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), while the levels of the lipid oxidation product malondialdehyde (MDA) remained unaffected. Nontargeted metabolomics analyses showed that MDA-19 interfered with multiple metabolic pathways affecting energy metabolism, such as alanine, aspartate, and glutamate metabolism; the citric acid cycle (TCA cycle), pantothenate, and coenzyme A biosynthesis; and purine metabolism. In conclusion, the present study provided the essential evidence for the neurotoxic effects of MDA-19, which was associated with impaired neurodevelopment, dysregulation of oxidative stress homeostasis, and altered energy metabolism.
随着全球对合成大麻素的监管日益严格，非法商贩越来越多地转向新型结构的合成大麻素来逃避法律审查。新型合成大麻素MDA-19在体内对2型大麻素受体表现出显著的激动作用，并在非法市场上呈现出新兴的滥用趋势。然而，关于MDA-19毒理学效应的研究仍然匮乏少。在本研究中，我们将斑马鱼胚胎暴露于浓度为1、10和20mg/L的MDA-19溶液中5天，以研究MDA-19对神经发育、行为、氧化应激和代谢组学的影响。结果显示，暴露于10mg/L和20mg/L的MDA-19会加速斑马鱼胚胎孵化，但会导致体长缩短，且不影响死亡率或畸形率。此外，暴露于所有浓度的MDA-19都会导致斑马鱼游泳能力下降和活动时间减少。暴露于MDA-19的转基因斑马鱼（hb9-GFP）表现出脊髓运动神经元发育受损。值得注意的是，暴露于20mg/L的MDA-19会增加斑马鱼体内活性氧（ROS）水平，并提高超氧化物歧化酶（SOD）和过氧化氢酶（CAT）等抗氧化酶的活性，而脂质氧化产物丙二醛（MDA）的水平则不受影响。非靶向代谢组学分析表明，MDA-19干扰了多个影响能量代谢的代谢途径，如丙氨酸、天冬氨酸和谷氨酸代谢；柠檬酸循环（TCA循环）、泛酸和辅酶A生物合成；以及嘌呤代谢。总之，本研究为MDA-19的神经毒性作用提供了重要证据，其与神经发育受损、氧化应激稳态失调和能量代谢改变有关。
