Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6
Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6
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DOI：
10.1124/mol.58.6.1247
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发表时间：
2000-12-01
影响因子：
3.6
通讯作者：
Cadet, JL
中科院分区：
文献类型：
--
作者：
Ladenheim, B;Krasnova, IN;Cadet, JL
越来越多的证据表明，细胞凋亡是甲基苯丙胺(METH)神经毒性中细胞死亡的主要机制。神经免疫成分参与了损伤或化学损伤后的细胞凋亡死亡，这表明细胞因子可能在冰毒效应中发挥作用。在目前的研究中，我们检测了IL-6基因敲除(IL-6-/-)小鼠中IL-6的缺失是否可以提供对抗冰毒诱导的神经毒性的保护。给予冰毒后，野生型小鼠尾壳核(CPU)和大脑皮层中[I-125]RTI-121标记的多巴胺转运体显著减少，CPU和额叶皮质中的多巴胺耗竭。然而，在IL-6-/-动物中，这些冰毒诱导的效应显著减弱。冰毒还导致野生型小鼠CPU和海马区的5-羟色胺水平下降，但在IL-6-/-动物中没有观察到下降。此外，在野生型动物中，METH诱导海马CA3区和黑质网状结构的[I-125]RTI-55标记的5-羟色胺转运体减少，而在CPU和扣带皮质的5-羟色胺转运体增加，这在IL-6-/-小鼠中都被减弱。此外，通过[H-3]PK-11195结合测定，冰毒引起野生型小鼠中央脑和大脑皮层胶质细胞增多；在IL-6-/-动物中，这种胶质反应几乎完全被抑制。对冰毒诱导的DNA断裂也有显著的保护作用，通过大脑皮层中末端脱氧核苷酸转移酶介导的dUTP缺口末端标记(TUNEL)细胞的数量来衡量。在IL-6-/-小鼠中观察到的对冰毒的保护作用不是由于温度升高或野生型和突变动物中冰毒积累的差异造成的。因此，这些观察结果支持IL-6可能在冰毒的神经毒性中发挥重要作用的命题。
Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absence of IL-6 in knockout (IL-6-/-) mice could provide protection against METH-induced neurotoxicity. Administration of METH resulted in a significant reduction of [I-125] RTI-121-labeled dopamine transporters in the caudate-putamen (CPu) and cortex as well as depletion of dopamine in the CPu and frontal cortex of wild-type mice. However, these METH-induced effects were significantly attenuated in IL-6-/- animals. METH also caused a decrease in serotonin levels in the CPu and hippocampus of wild-type mice, but no reduction was observed in IL-6-/- animals. Moreover, METH induced decreases in [I-125]RTI-55-labeled serotonin transporters in the hippocampal CA3 region and in the substantia nigra-reticulata but increases in serotonin transporters in the CPu and cingulate cortex in wild-type animals, all of which were attenuated in IL-6-/- mice. Additionally, METH caused increased gliosis in the CPu and cortices of wild-type mice as measured by [H-3] PK-11195 binding; this gliotic response was almost completely inhibited in IL-6-/- animals. There was also significant protection against METH-induced DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled (TUNEL) cells in the cortices. The protective effects against METH toxicity observed in the IL-6-/- mice were not caused by differences in temperature elevation or in METH accumulation in wild-type and mutant animals. Therefore, these observations support the proposition that IL-6 may play an important role in the neurotoxicity of METH.