Bowyer John F, Ali Syed
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
Synapse. 2006 Dec 1;60(7):521-32. doi: 10.1002/syn.20324.
Histological examination of brain after a single high (40 mg/kg) dose of D-methamphetamine (METH) was used to determine the relationships between blood-brain barrier (BBB) disruption, hyperthermia, intense seizure activity, and extensive degeneration that this exposure often produces. In very hyperthermic mice (body temperatures > 40.5 degrees C) exhibiting status epilepticus, increase in mouse IgG immunoreactivity (IgGIR) in the medial and ventral amygdala was observed within 90 min after METH exposure. In a few instances, where body temperature was in the 40.0 degrees C range, such IgGIR was also seen in animals that had exhibited status epilepticus. Variable increases in IgGIR, which correlated with neurodegeneration, also occurred within 12 h in the hippocampus, indicating BBB disruption in this region also. Degenerating neurons, Fluoro-Jade C (FJ-C) labeled, were first detected 4 h after METH in the amygdala and hippocampus. Extensive neurodegeneration occurred in the amygdaloid and hippocampal pyramidal cell regions in animals with marked IgGIR increase in these regions by 12 and 24 h after METH. A very rapid activation of brain microglia and/or infiltration of macrophages in regions of notable IgGIR increase with intense neurodegeneration were seen within 24 h. The phagocytosis rate of neurons in the hippocampus was so rapid that FJ-C labeling was virtually nonexistent 3 days after METH. METH did not produce IgGIR increase or neurodegeneration in the limbic regions in the absence of hyperthermia and seizures. Thus, high doses of METH can cause damage to the BBB when hyperthermia occurs, resulting in rapid and extensive hippocampal and amygdalar damage. The BBB disruption in the medial amygdala occurs first, and may well be contributing to the induction and severity of seizures, while BBB disruption in the hippocampus is likely a result of the seizures and hyperthermia. This hippocampal damage should be sufficient to compromise learning and memory.
单次高剂量（40毫克/千克）的D-甲基苯丙胺（METH）给药后，对大脑进行组织学检查，以确定血脑屏障（BBB）破坏、体温过高、强烈的癫痫活动以及这种暴露常产生的广泛变性之间的关系。在体温极高（体温>40.5摄氏度）且表现为癫痫持续状态的小鼠中，在METH暴露后90分钟内观察到内侧和腹侧杏仁核中小鼠IgG免疫反应性（IgGIR）增加。在少数情况下，体温在40.0摄氏度范围内时，在表现为癫痫持续状态的动物中也观察到了这种IgGIR。与神经变性相关的IgGIR也在12小时内在海马体中出现了不同程度的增加，表明该区域也存在血脑屏障破坏。经Fluoro-Jade C（FJ-C）标记的变性神经元在METH给药后4小时首次在杏仁核和海马体中被检测到。在METH给药后12小时和24小时，在这些区域IgGIR显著增加的动物中，杏仁核和海马体锥体细胞区域出现了广泛的神经变性。在24小时内，在IgGIR显著增加且伴有强烈神经变性的区域，观察到脑小胶质细胞的快速激活和/或巨噬细胞的浸润。海马体中神经元的吞噬速度非常快，以至于在METH给药3天后，FJ-C标记几乎不存在。在没有体温过高和癫痫发作的情况下，METH不会导致边缘区域的IgGIR增加或神经变性。因此，当体温过高发生时，高剂量的METH会对血脑屏障造成损害，导致海马体和杏仁核迅速且广泛的损伤。内侧杏仁核中的血脑屏障破坏首先发生，很可能促成了癫痫发作的诱发和严重程度，而海马体中的血脑屏障破坏可能是癫痫发作和体温过高的结果。这种海马体损伤应该足以损害学习和记忆。
