Neurotoxic-related changes in tyrosine hydroxylase, microglia, myelin, and the blood-brain barrier in the caudate-putamen from acute methamphetamine exposure
Neurotoxic-related changes in tyrosine hydroxylase, microglia, myelin, and the blood-brain barrier in the caudate-putamen from acute methamphetamine exposure
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DOI：
10.1002/syn.20478
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发表时间：
2008-03-01
期刊：
影响因子：
2.3
通讯作者：
Schmued, Larry C.
中科院分区：
文献类型：
--
作者：
Bowyer, John F.;Robinson, Bonnie;Schmued, Larry C.
在接触高剂量甲基苯丙胺 (METH) 后测定尾壳核 (CPu) 组织学形态的变化，以阐明 BBB 破坏是否在 CPu 神经毒性中起作用。这是通过评估成年雄性小鼠在 METH 后 90 分钟、4 小时、12 小时、1 天和 3 天的酪氨酸羟化酶免疫反应性 (TH-IR)、异凝集素 B4 反应性、黑金 II (BG-II) 和氟玉 C (FJ-C) 染色以及对小鼠免疫球蛋白 G (IgG-IR) 的免疫反应性来完成的 接触。 IgG-IR 表明，在神经变性发生后的时间点，CPu 中的 BBB 仅发生适度改变，并且依赖于高热和癫痫持续状态。在血管周围区域观察到的适度的 CPu IgG-IR 变化表明，在 METH 后 1 天或更长时间，一些 CPu 小胶质细胞上存在免疫球蛋白。 METH 后 4 小时，CPu 损伤的第一个迹象是 TH-IR 轴突肿胀、髓磷脂损伤和一些神经元退化。 TH-IR 的丧失取决于高热，而不是癫痫发作或 CPu 神经变性，并且在 12 小时内，整个 CPu 中几乎不存在 TH-IR。令人惊讶的是，CPu 中 FJ-C 标记（退化）轴突的迹象仅出现在明显的体细胞神经退化区域，并且与 TH-IR 损失无关。直到使用 METH 后 1 天或更长时间，小胶质细胞才发生激活。总之，在单次高剂量冰毒暴露中，CPu 内的主要 BBB 破坏并不直接导致神经毒性。然而，杏仁核 BBB 破坏产生或加剧的癫痫发作活动可显着增加 CPu 体细胞神经变性（但不影响多巴胺 (DA) 末端损伤）。小胶质细胞激活的时间过程表明了 TH-IR 丢失后对神经退行性变、髓磷脂损伤和/或受损 DA 末端的反应。
Changes in the histological morphology of the caudate-putamen (CPu) were determined after a high-dose methamphetamine (METH) exposure in an effort to elucidate whether BBB disruption plays a role in CPu neurotoxicity. This was accomplished by evaluating the tyrosine hydroxylase immunoreactivity (TH-IR), isolectin B4 reactivity, Black Gold II (BG-II) and Fluoro-Jade C (FJ-C) staining, and immunoreactivity to mouse immunoglobulin G (IgG-IR) in adult male mice at 90-min, 4-h, 12-h, 1-day, and 3-day post-METH exposure. The IgG-IR indicated that the BBB was only modestly altered in the CPu at time points after neurodegeneration occurred and dependent on hyperthermia and status epilepticus. The modest CPu IgG-IR changes observed in the perivascular areas indicated that immunoglobulins were present on some CPu microglia 1 day or more after METH. The first signs of CPu damage were swellings in the TH-IR axons, myelin damage, and a few degenerating neurons at 4-h post-METH. The loss of TH-IR was dependent on hyperthermia but not seizures or CPu neurodegeneration, and the TH-IR was virtually absent throughout the CPu within 12 h. Surprisingly, signs of FJ-C labeling (degenerating) axons in the CPu were seen only in the regions of pronounced somatic neurodegeneration and independent of TH-IR loss. Microglial activation did not occur until 1 day or more post-METH. In summary, a major BBB disruption within the CPu does not directly contribute to neurotoxicity in this single high-dose METH exposure. However, seizure activity produced or exacerbated by amygdalar BBB disruption can significantly increase CPu somatic neurodegeneration (but not affect dopamine (DA) terminal damage). The time course of microglial activation indicates a response to the neurodegeneration, myelin damage, and/or damaged DA terminals after loss of TH-IR.