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The time course of blood brain barrier leakage and its implications on the progression of methamphetamine-induced seizures
NeuroToxicology ( IF 3.4 ) Pub Date : 2018-09-30 , DOI: 10.1016/j.neuro.2018.09.008
John F. Bowyer , Karen M. Tranter , Bonnie L. Robinson , Joseph P. Hanig , Madeline G. Faubion , Sumit Sarkar

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 mm2) 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.



中文翻译:

血脑屏障渗漏的时程及其对甲基苯丙胺诱发的癫痫发作的影响

这些实验的最初目的是确定:1​​)血脑屏障(BBB)的破坏是否是METH诱发的癫痫发作的原因或结果;2)随着癫痫发作的进展,BBB受到破坏的所有大脑区域;3)体温与血管渗漏和神经变性之间的相关性。在初步实验后添加第四个目标,以确定在成年雄性C57 B6 J(杰克逊实验室,JAX)与C57 B6N(Charles River,CR)小鼠中是否存在亚株差异,这涉及其对BBB分解和癫痫发作严重程度的敏感性。在第一个“最大”强度的肌阵挛性惊厥(MCT)中,跨BBB的IgG浸润程度不同(≤1 mm 2)在嗅觉系统(OS)相关区域以及丘脑,下丘脑和新皮层中很明显。持续性行为性癫痫发作(CBS)形成时,纹状体终末,隔层和更多的杏仁核内侧核的OS相关区域中IgG的浸润区域和下丘脑显着增加。接受METH且体温≥40°C的小鼠具有MCT或CBS的IgG浸润,但高于40°C的峰值体温并没有显着增加IgG浸润。在JAX和CR小鼠中,≥6 h见到的神经变性都局限于OS,并且在后内侧皮质杏仁核中最为明显。仅在JAX小鼠中观察到前中膜(tenia tecta)的神经退行性变。我们假设METH诱发的高血压和高热导致OS脑区域的BBB分解和其他血管功能障碍,导致OS过度兴奋。OS神经网络的激发导致癫痫发作的发展。这些癫痫发作继而加剧了体温过高所产生的能量消耗和活性氧应激,进一步损害了血脑屏障和血管功能。这些事件形成周期性循环,导致癫痫发作活动和神经毒性不断增加。

更新日期:2018-09-30
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