Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, 72079, AR, USA.
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, 72079, AR, USA.
Neurotoxicology. 2018 Dec;69:130-140. doi: 10.1016/j.neuro.2018.09.008. Epub 2018 Sep 30.
The initial goals of these experiments were to determine: 1) if blood-brain barrier (BBB) breakdown was a cause or an effect of METH-induced seizures; 2) all the brain regions where BBB is disrupted as seizures progress; and 3) the correlations between body temperature and vascular leakage and neurodegeneration. A fourth objective was added after initial experimentation to determine if sub-strain differences existed in adult male C57 B6 J (Jackson laboratories, JAX) versus C57 B6N (Charles River, CR) mice involving their susceptibility to BBB breakdown and seizure severity. With the 1st "maximal" intensity myoclonic-tonic seizure (MCT) varying degrees of IgG infiltration across the BBB (≤1 mm) were prominent in olfactory system (OS) associated regions and in thalamus, hypothalamus and neocortex. IgG infiltration areas in the OS-associated regions of the bed nucleus of the stria terminalis, septum and more medial amygdala nuclei, and the hypothalamus were increased significantly by the time continuous behavioral seizures (CBS) developed. Mice receiving METH that had body temperatures of ≥40 °C had IgG infiltration along with MCT or CBS but peak body temperatures above 40 °C did not significantly increase IgG infiltration. Neurodegeneration seen at ≥6 h was restricted to the OS in both JAX and CR mice and was most prominent in the posteromedial cortical amygdaloid nucleus. Neurodegeneration in the anterior septum (tenia tecta) was seen only in the JAX mice. We hypothesize that METH-induced hypertension and hyperthermia lead to BBB breakdown and other vascular dysfunctions in the OS brain regions resulting in OS hyperexcitation. Excitation of the OS neural network then leads to the development of seizures. These seizures in turn exacerbate the energy depletions and the reactive oxygen stress produced by hyperthermia further damaging the BBB and vascular function. These events form a recurrent cycle that results in ever increasing seizure activity and neurotoxicity.
1）血脑屏障（BBB）的破坏是 METH 诱导的癫痫发作的原因还是结果；2）随着癫痫发作的进展，所有 BBB 被破坏的脑区；3）体温与血管渗漏和神经退行性变之间的相关性。在最初的实验之后，增加了第四个目标，以确定成年雄性 C57 B6J（杰克逊实验室，JAX）与 C57 B6N（查尔斯河，CR）小鼠之间是否存在亚系差异，涉及它们对 BBB 破坏和癫痫发作严重程度的易感性。在第 1 次“最大”强度肌阵挛性抽搐（MCT）中，BBB 跨壁的 IgG 浸润程度不一（≤1mm），在嗅觉系统（OS）相关区域和丘脑、下丘脑和新皮质中最为明显。在终纹床核、隔核和内侧杏仁核核以及下丘脑的 OS 相关区域，当连续行为性癫痫发作（CBS）发展时，IgG 浸润面积显著增加。体温≥40°C 的接受 METH 的小鼠有 IgG 浸润，伴有 MCT 或 CBS，但体温峰值超过 40°C 不会显著增加 IgG 浸润。≥6 h 时观察到的神经退行性变仅限于 JAX 和 CR 小鼠的 OS，在中后皮质杏仁核中最为明显。仅在 JAX 小鼠中观察到前隔核（终板）的神经退行性变。我们假设，METH 诱导的高血压和体温升高导致 OS 脑区的 BBB 破坏和其他血管功能障碍，导致 OS 过度兴奋。OS 神经网络的兴奋继而导致癫痫发作的发展。这些癫痫发作反过来又加剧了由体温升高引起的能量耗竭和活性氧应激，进一步损害 BBB 和血管功能。这些事件形成了一个反复循环，导致癫痫活动和神经毒性不断增加。
