Division of Basic Medical Sciences, Mercer University School of Medicine Macon, GA, USA.
Front Syst Neurosci. 2011 May 9;5:27. doi: 10.3389/fnsys.2011.00027. eCollection 2011.
Treatment with multiple high doses of methamphetamine (METH) can induce oxidative damage, including dopamine (DA)-mediated reactive oxygen species (ROS) formation, which may contribute to the neurotoxic damage of monoamine neurons and long-term depletion of DA in the caudate putamen (CPu) and substantia nigra pars compacta (SNpc). Malondialdehyde (MDA), a product of lipid peroxidation by ROS, is commonly used as a marker of oxidative damage and treatment with multiple high doses of METH increases MDA reactivity in the CPu of humans and experimental animals. Recent data indicate that MDA itself may contribute to the destruction of DA neurons, as MDA causes the accumulation of toxic intermediates of DA metabolism via its chemical modification of the enzymes necessary for the breakdown of DA. However, it has been shown that in human METH abusers there is also increased MDA reactivity in the frontal cortex, which receives relatively fewer DA afferents than the CPu. These data suggest that METH may induce neuronal damage regardless of the regional density of DA or origin of DA input. The goal of the current study was to examine the modification of proteins by MDA in the DA-rich nigrostriatal and mesoaccumbal systems, as well as the less DA-dense cortex and hippocampus following a neurotoxic regimen of METH treatment. Animals were treated with METH (10 mg/kg) every 2 h for 6 h, sacrificed 1 week later, and examined using immunocytochemistry for changes in MDA-adducted proteins. Multiple, high doses of METH significantly increased MDA immunoreactivity (MDA-ir) in the CPu, SNpc, cortex, and hippocampus. Multiple METH administration also increased MDA-ir in the ventral tegmental area and nucleus accumbens. Our data indicate that multiple METH treatment can induce persistent and widespread neuronal damage that may not necessarily be limited to the nigrostriatal DA system.
多剂量 methamphetamine（METH）治疗可诱导氧化损伤，包括多巴胺（DA）介导的活性氧（ROS）形成，这可能导致单胺能神经元的神经毒性损伤和纹状体尾壳核（CPu）和黑质致密部（SNpc）中 DA 的长期耗竭。丙二醛（MDA）是 ROS 引发的脂质过氧化产物，通常用作氧化损伤的标志物，多次大剂量 METH 治疗会增加 CPu 中 MDA 的反应性，无论是在人类还是实验动物中。最近的数据表明，MDA 本身可能导致 DA 神经元的破坏，因为 MDA 通过化学修饰 DA 分解所需的酶，导致 DA 代谢的有毒中间产物积累。然而，已经表明，在人类 METH 滥用者中，额皮质中 MDA 的反应性也会增加，额皮质接收的 DA 传入比 CPu 少。这些数据表明，METH 可能会诱导神经元损伤，而与 DA 的区域密度或 DA 输入的来源无关。本研究的目的是检查 MDA 在富含 DA 的黑质纹状体和中脑边缘系统以及 DA 密度较低的皮质和海马中的蛋白质修饰，以及在 METH 治疗的神经毒性方案后。动物接受 METH（10mg/kg）每 2 小时一次，共 6 小时，1 周后处死，并使用免疫细胞化学检查 MDA 加合物蛋白的变化。多次大剂量 METH 显著增加了 CPu、SNpc、皮质和海马中的 MDA 免疫反应性（MDA-ir）。多次 METH 给药还增加了腹侧被盖区和伏隔核中的 MDA-ir。我们的数据表明，多次 METH 治疗可诱导持久且广泛的神经元损伤，这种损伤不一定局限于黑质纹状体 DA 系统。
