Department of Radiology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital/Center. No, 519 Kunzhou Road, Xishan District, Kunming, 650118, Yunnan, People's Republic of China.
Department of PET/CT Center, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital/Center. No, 519 Kunzhou Road, Xishan District, Kunming, 650118, Yunnan, People's Republic of China.
Neurotox Res. 2022 Aug;40(4):1070-1085. doi: 10.1007/s12640-022-00533-3. Epub 2022 Jun 27.
Heroin is a highly addictive drug that causes axonal damage. Here, manganese-enhanced magnetic resonance imaging (MEMRI) was used to dynamically monitor axonal transport at different stages of heroin addiction. Rat models of heroin addiction (HA) and prolonged heroin addiction (PHA) were established by injecting rats with heroin at different stages. Heroin-induced learning and memory deficits were evaluated in the Morris water maze (MWM), and MEMRI was used to dynamically evaluate axonal transport in the olfactory pathway. The expression of proteins related to axonal structure and function was also assessed by Western blotting. Transmission electron microscopy (TEM) was used to observe ultrastructural changes, and protein levels of neurofilament heavy chain (NF-H) were analyzed by immunofluorescence staining. HA rats, especially PHA rats, exhibited worse spatial learning and memory than control rats. Compared with HA rats and control rats, PHA rats exhibited significantly longer escape latencies, significantly fewer platform-location crossings, and significantly more time in the target quadrant during the MWM test. Mn transport was accelerated in HA rats. PHA rats exhibited severely reduced Mn transport, and the axonal transport rate (ATR) was significantly lower in these rats than in control rats (P < 0.001). The levels of cytoplasmic dynein and kinesin-1 were significantly decreased in the PHA group than in the control group (P < 0.001); additionally, the levels of energy-related proteins, including cytochrome c oxidase (COX) IV and ATP synthase subunit beta (ATPB), were lower in the PHA group (P < 0.001). The brains of heroin-exposed rats displayed an abnormal ultrastructure, with neuronal apoptosis and mitochondrial dysfunction. Heroin exposure decreased the expression of NF-H, as indicated by significantly reduced staining intensities in tissues from HA and PHA rats (P < 0.05). MEMRI detected axonal transport dysfunction caused by long-term repeated exposure to heroin. The main causes of axonal transport impairment may be decreases in the levels of motor proteins and mitochondrial dysfunction. This study shows that MEMRI is a potential tool for visualizing axonal transport in individuals with drug addictions, providing a new way to evaluate addictive encephalopathy.
海洛因是一种高度成瘾的毒品，会导致轴突损伤。在这里，锰增强磁共振成像（MEMRI）被用于动态监测海洛因成瘾不同阶段的轴突运输。通过在不同阶段向大鼠注射海洛因，建立了海洛因成瘾（HA）和长期海洛因成瘾（PHA）大鼠模型。在 Morris 水迷宫（MWM）中评估海洛因诱导的学习和记忆缺陷，并用 MEMRI 动态评估嗅觉通路中的轴突运输。通过 Western 印迹评估与轴突结构和功能相关的蛋白质的表达。透射电子显微镜（TEM）用于观察超微结构变化，并通过免疫荧光染色分析神经丝重链（NF-H）的蛋白水平。与对照组相比，HA 大鼠，尤其是 PHA 大鼠，表现出更差的空间学习和记忆能力。与 HA 大鼠和对照组相比，PHA 大鼠在 MWM 测试中表现出明显更长的逃避潜伏期、明显更少的平台位置穿越次数和明显更多的目标象限时间。HA 大鼠的 Mn 转运加速。PHA 大鼠的 Mn 转运明显减少，其轴突转运率（ATR）明显低于对照组（P<0.001）。细胞质动力蛋白和驱动蛋白-1 的水平在 PHA 组明显低于对照组（P<0.001）；此外，细胞色素 c 氧化酶（COX）IV 和 ATP 合酶亚基β（ATPB）等能量相关蛋白的水平在 PHA 组较低（P<0.001）。海洛因暴露大鼠的大脑显示出异常的超微结构，伴有神经元凋亡和线粒体功能障碍。海洛因暴露降低了 NF-H 的表达，HA 和 PHA 大鼠组织的染色强度明显降低（P<0.05）。MEMRI 检测到长期重复暴露于海洛因引起的轴突运输功能障碍。轴突运输受损的主要原因可能是运动蛋白水平降低和线粒体功能障碍。本研究表明，MEMRI 是一种可视化药物成瘾个体轴突运输的潜在工具，为评估成瘾性脑病提供了一种新方法。
