Potential new insights into the molecular mechanisms of methamphetamine-induced neurodegeneration.-猫眼课题宝

DOI：

10.1037/e495572006-011

发表时间：

1997

期刊：

NIDA research monograph

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

M. Wrona;Zhaoliang Yang;Fa Zhang;G. Dryhurst

如果甲基苯丙胺引起HO。由于在多巴胺能轴突终末内形成，预期5-HT的最终氧化不仅产生5，6-DHT，而且产生T-4，5-D、7-S-Glu-T-4，5-D、6，8和7，7 ′-D（图1），其中至少三种（T-4，5-D、7-S-Glu-T-4，5-D和6）在小鼠脑中是致死的。此外，在体外氧化5-HT的HO形成的几个中间体/产品。在预期会产生O2-的反应中，易于自动氧化（4，5-DHT、5，6-DHT、5、7和9）或氧化还原循环（T-4，5-D、6，8，7，7 '-D、7-S-Glu-T-4，5-D）。和/或H2 O2作为副产物。这些副产物在痕量水平的过渡金属离子催化剂的存在下将容易地转化为HO。（Walling 1975; Halliwell and Gutteridge 1984）。结合这些推定的5-HT和HO的异常氧化代谢物。形成反应可能有助于肾上腺素能神经末梢的变性。同样，甲基苯丙胺诱导的HO的神经元内形成。在多巴胺能末梢中，可以预期不仅产生6-OHDA（以及2-OHDA和5-OHDA，图3），而且产生5，-S-CyS-DA和5-S-Glu-DA，DHBT 17和其他更复杂的二氢苯并噻嗪的前体（图4）。DHBTs 17至19在小鼠脑中是致命的，尽管目前这种毒性的生化/化学机制和受影响的特定神经系统尚不清楚。然而，5-S-CyS-DA和17至19比DA更容易氧化，并且后一种DHBTs似乎能够进行氧化还原循环反应（Zhang和Dryhurst 1994）。因此，HO。由甲基苯丙胺诱导的多巴胺能神经末梢中的DA介导的氧化可能预期产生异常的氧化代谢物，其（作为自氧化和氧化还原循环反应的结果）增强O2-的形成。和/或H2 O2，然后是HO。和神经元损伤。先前讨论的许多证据表明，DA的异常代谢物（除6-OHDA外）可能导致甲基苯丙胺诱导的多巴胺能末梢和多巴胺能末梢变性。类似地，5-HT的异常代谢物（不同于或除了5，6-DHT之外）可能涉及多巴胺能和多巴胺能末梢以及躯体感觉皮层中细胞体亚群的变性。实验证据表明，甲基苯丙胺引起的一些神经退行性作用是由NMDA和GABA受体介导的。因此，研究5-HT（图1和图2）和DA（图4和图5）的假定异常氧化代谢产物对多巴胺能、多巴胺能和其他神经元系统的神经毒性及其与NMDA、GABA和其他脑受体的相互作用将具有相当大的意义。一个中心问题涉及甲基苯丙胺可能引起神经元内氧自由基形成的机制，氧自由基似乎在该药物引起的整体神经变性过程中起重要作用（DeVito和瓦格纳，1989; Cadet et al. 1994）。一旦5-HT的推定氧化代谢产物如T-4，5-D、7-S-Glu-T-4，5-D、5，6-DHT、6，8和7，7 '-D（图1）在神经元内形成，自氧化/氧化还原循环反应原则上应能够产生O2-。和/或H2 O2，HO的前体。类似地，神经元内6-OHDA、5-S-CyS-DA和DHBTs 17至19和22的形成也预期会增强O2-的通量升高。H2 O2和HO。这是由于这些推定的异常代谢物的容易的自氧化/氧化还原循环反应。在人类和其他哺乳动物大脑富含DA的区域中存在极低浓度的5-S-CyS-DA，这表明自氧化（Rosengren等人，1985; Fornstedt等人，1986，1989，1990）或其他形式的DA氧化是体内的正常反应。此外，现有证据表明，细胞质DA被氧化以产生5-S-CyS-DA（Fornstedt等人，1989; Fornstedt和

In the event that methamphetamine evokes HO. formation within serotonergic axon terminals, the resultant oxidation of 5-HT would be expected to generate not only 5,6-DHT but also T-4,5-D, 7-S-Glu-T-4,5-D, 6, 8, and 7,7'-D (figure 1), at least three of which (T-4,5-D, 7-S-Glu-T-4,5-D, and 6) are lethal in mouse brain. Furthermore, several intermediates/products formed in the in vitro oxidation of 5-HT by HO. are readily autoxidized (4,5-DHT, 5,6-DHT, 5, 7, and 9) or redox cycled (T-4,5-D, 6, 8, 7,7'-D, 7-S-Glu-T-4,5-D) in reactions that would be expected to yield O2-. and/or H2O2 as byproducts. These byproducts, in the presence of trace levels of transition metal ion catalysts, would be readily converted into HO. (Walling 1975; Halliwell and Gutteridge 1984). Together these putative aberrant oxidative metabolites of 5-HT and HO.-forming reactions might contribute to the degeneration of serotonergic nerve terminals. Similarly, the methamphetamine-induced intraneuronal formation of HO. in dopaminergic terminals might be expected to generate not only 6-OHDA (and 2-OHDA and 5-OHDA, figure 3) but also 5,-S-CyS-DA and 5-S-Glu-DA, precursors of DHBT 17 and other more complex dihydrobenzothiazines (figure 4). DHBTs 17 to 19 are lethal in mouse brain, although at this time the biochemical/chemical mechanisms underlying this toxicity and specific neuronal systems affected are unknown. However, 5-S-CyS-DA and 17 to 19 are much more easily oxidized than DA, and the latter DHBTs appear to be capable of redox cycling reactions (Zhang and Dryhurst 1994). Thus, the HO.-mediated oxidation of DA in dopaminergic nerve terminals induced by methamphetamine might be expected to generate aberrant oxidative metabolites that (as a result of autoxidation and redox cycling reactions) potentiate formation of O2-. and/or H2O2, and then HO. and neuronal damage. A number of lines of evidence, discussed previously, suggest that aberrant metabolite(s) of DA (other than or in addition to 6-OHDA) might contribute to the methamphetamine-induced degeneration of not only dopaminergic terminals but also serotonergic terminals. Similarly, aberrant metabolite(s) of 5-HT (other than or in addition to 5,6-DHT) might be involved in the degeneration of serotonergic and dopaminergic terminals and a subpopulation of cell bodies in the somatosensory cortex. Experimental evidence indicates that some of the neurodegenerative effects evoked by methamphetamine are mediated by NMDA and GABA receptors. Thus, it will be of considerable interest to investigate the neurotoxicity of putative aberrant oxidative metabolites of 5-HT (figures 1 and 2) and DA (figures 4 and 5) towards serotonergic, dopaminergic, and other neuronal systems and their interactions with NMDA, GABA, and other brain receptors. A central question relates to mechanisms by which methamphetamine might evoke the intraneuronal formation of oxygen radicals that appear to play important roles in the overall neurodegenerative processes evoked by this drug (DeVito and Wagner 1989; Cadet et al. 1994). Once putative oxidative metabolites of 5-HT such as T-4,5-D, 7-S-Glu-T-4,5-D, 5,6-DHT, 6, 8, and 7,7'-D (figure 1) are formed intraneuronally, autoxidation/redox cycling reactions should, in principle, be capable of generating O2-. and/or H2O2, the precursors of HO.. Similarly, intraneuronal formation of 6-OHDA, 5-S-CyS-DA, and DHBTs 17 to 19 and 22 would also be expected to potentiate elevated fluxes of O2-., H2O2, and HO. as a result of the facile autoxidation/redox cycling reactions of these putative aberrant metabolites. The presence of very low concentrations of 5-S-CyS-DA in DA-rich regions of human and other mammalian brains suggest that autoxidation (Rosengren et al. 1985; Fornstedt et al. 1986, 1989, 1990) or perhaps some other form of DA oxidation is a normal reaction in vivo. Furthermore, available evidence suggests that it is cytoplasmic DA that is oxidized to give 5-S-CyS-DA (Fornstedt et al. 1989; Fornstedt and

Potential new insights into the molecular mechanisms of methamphetamine-induced neurodegeneration.

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