Bowyer John F, Sarkar Sumit, Tranter Karen M, Hanig Joseph P, Miller Diane B, O'Callaghan James P
Division of Neurotoxicology, National Center for Toxicology/FDA, Jefferson, AR, 72079, USA.
National Center for Toxicological Research/FDA, 3900 NCTR Road, HFT-132, Jefferson, AR, 72079, USA.
J Neuroinflammation. 2016 Mar 12;13(1):64. doi: 10.1186/s12974-016-0526-6.
Brain microglial activations and damage responses are most commonly associated with neurodegeneration or systemic innate immune system activation. Here, we used histological methods to focus on microglial responses that are directed towards brain vasculature, previously undescribed, after a neurotoxic exposure to methamphetamine.
Male rats were given doses of methamphetamine that produce pronounced hyperthermia, hypertension, and toxicity. Identification of microglia and microglia-like cells (pericytes and possibly perivascular cells) was done using immunoreactivity to allograft inflammatory factor 1 (Aif1 a.k.a Iba1) and alpha M integrin (Itgam a.k.a. Cd11b) while vasculature endothelium was identified using rat endothelial cell antigen 1 (RECA-1). Regions of neuronal, axonal, and nerve terminal degeneration were determined using Fluoro-Jade C.
Dual labeling of vasculature (RECA-1) and microglia (Iba1) showed a strong association of hypertrophied cells surrounding and juxtaposed to vasculature in the septum, medial dorsal hippocampus, piriform cortex, and thalamus. The Iba1 labeling was more pronounced in the cell body while Cd11b more so in the processes of activated microglia. These regions have been previously identified to have vascular leakage after neurotoxic methamphetamine exposure. Dual labeling with Fluoro-Jade C and Iba1 indicated that there was minimal or no evidence of neuronal damage in the septum and hippocampus where many hypertrophied Iba1-labeled cells were found to be associated with vasculature. Although microglial activation around the prominent neurodegeneration was found in the thalamus, there were also many examples of activated microglia associated with vasculature.
The data implicate microglia, and possibly related cell types, in playing a major role in responding to methamphetamine-induced vascular damage, and possibly repair, in the absence of neurodegeneration. Identifying brain regions with hypertrophied/activated microglial-like cells associated with vasculature has the potential for identifying regions of more subtle examples of vascular damage and BBB compromise.
脑小胶质细胞激活和损伤反应最常与神经退行性变或全身先天性免疫系统激活相关。在此，我们使用组织学方法聚焦于在神经毒性暴露于甲基苯丙胺后针对脑脉管系统的小胶质细胞反应，这是此前未被描述过的。
给雄性大鼠给予能产生明显体温过高、高血压和毒性的甲基苯丙胺剂量。使用对同种异体移植炎症因子1（Aif1，又名Iba1）和αM整合素（Itgam，又名Cd11b）的免疫反应性来鉴定小胶质细胞和小胶质细胞样细胞（周细胞以及可能的血管周围细胞），而使用大鼠内皮细胞抗原1（RECA-1）来鉴定脉管系统内皮。使用氟玉髓C确定神经元、轴突和神经终末变性的区域。
脉管系统（RECA-1）和小胶质细胞（Iba1）的双重标记显示，在隔区、内侧背海马、梨状皮质和丘脑中，肥大细胞与脉管系统周围和并列存在着强烈关联。Iba1标记在细胞体中更明显，而Cd11b在活化小胶质细胞的突起中更明显。这些区域此前已被确定在神经毒性甲基苯丙胺暴露后存在血管渗漏。氟玉髓C和Iba1的双重标记表明，在隔区和海马中，尽管发现许多肥大的Iba1标记细胞与脉管系统相关，但几乎没有或没有神经元损伤的证据。虽然在丘脑中发现明显神经退行性变周围有小胶质细胞激活，但也有许多活化小胶质细胞与脉管系统相关的例子。
数据表明，在没有神经退行性变的情况下，小胶质细胞以及可能相关的细胞类型在应对甲基苯丙胺诱导的血管损伤及可能的修复中起主要作用。识别与脉管系统相关的肥大/活化小胶质细胞样细胞的脑区，有可能识别出血管损伤和血脑屏障受损更细微例子的区域。
