BACKGROUND Bacterial meningitis is a devastating central nervous system (CNS) infection with acute and long-term neurological consequences, including cognitive impairment. The aim of this study was to understand the association between activated microglia-induced neuroinflammation and post-meningitis cognitive impairment. METHOD Meningitis was induced in male Wistar rats by injecting Streptococcus pneumoniae into the brain through the cisterna magna, and rats were then treated with ceftriaxone. Twenty-four hours and 10 days after meningitis induction, rats were imaged with positron emission tomography (PET) using [11C]PBR28, a specific translocator protein (TSPO) radiotracer, to determine in vivo microglial activation. Following imaging, the expression of TSPO, cardiolipin, and cytochrome c, inflammatory mediators, oxidative stress markers, and glial activation markers were evaluated in the prefrontal cortex and hippocampus. Ten days after meningitis induction, animals were subjected to behavioral tests, such as the open-field, step-down inhibitory avoidance, and novel object recognition tests. RESULTS Both 24-h (acute) and 10-day (long-term) groups of rats demonstrated increased [11C]PBR28 uptake and microglial activation in the whole brain compared to levels in the control group. Although free from infection, 10-day group rats exhibited increased expression levels of cytokines and markers of oxidative stress, microglial activation (IBA-1), and astrocyte activation (GFAP) similar to those seen in the 24-h group. Acute meningitis induction also elevated TSPO, cytochrome c, and caspase-3 levels with no change in caspase-9 levels. Furthermore, upregulated levels of TSPO, cytochrome c, and caspase-3 and caspase-9 were observed in the rat hippocampus 10 days after meningitis induction with a simultaneous reduction in cardiolipin levels. Animals showed a cognitive decline in all tasks compared with the control group, and this impairment may be at least partially mediated by activating a glia-mediated immune response and upregulating TSPO. CONCLUSIONS TSPO-PET could potentially be used as an imaging biomarker for microglial activation and long-term cognitive impairment post-meningitis. Additionally, this study opens a new avenue for the potential use of TSPO ligands after infection-induced neurological sequelae.

中文翻译：

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来自体内PET研究的实验性脑膜炎证据表明，神经炎症轨迹先于认知障碍。

背景技术细菌性脑膜炎是破坏性的中枢神经系统（CNS）感染，具有急性和长期的神经系统后果，包括认知障碍。这项研究的目的是了解活化的小胶质细胞诱导的神经炎症与脑膜炎后认知障碍之间的关系。方法将雄性Wistar大鼠通过大水罐注入肺炎链球菌诱发脑膜炎，然后用头孢曲松钠治疗。脑膜炎诱发后24小时10天，使用正电子发射断层扫描（PET）使用[11C] PBR28（一种特定的转运蛋白（TSPO）放射性示踪剂）对大鼠进行成像，以确定体内的小胶质细胞活化。成像后，TSPO，心磷脂和细胞色素c，炎症介质，氧化应激标志物的表达，在前额叶皮层和海马区评估神经胶质激活标志物。诱发脑膜炎十天后，对动物进行行为测试，例如开阔地域，降压抑制回避和新颖的物体识别测试。结果与对照组相比，大鼠的24小时（急性）和10天（长期）组均显示全脑的[11C] PBR28摄取和小胶质细胞活化增加。尽管没有感染，但是10天组大鼠的细胞因子表达水平和氧化应激，小胶质细胞活化（IBA-1）和星形胶质细胞活化（GFAP）的表达水平与24小时组相似。急性脑膜炎诱导也升高TSPO，细胞色素c和caspase-3水平，而caspase-9水平没有变化。此外，TSPO，细胞色素c，脑膜炎诱导后10天，在大鼠海马中观察到caspase-3和caspase-3和caspase-9的合成，同时心磷脂水平降低。与对照组相比，动物在所有任务中均表现出认知能力下降，并且这种损伤至少可以通过激活神经胶质介导的免疫反应和上调TSPO来部分介导。结论TSPO-PET可能被用作小胶质细胞活化和脑膜炎后长期认知障碍的影像学生物标志物。此外，这项研究为感染诱导的神经系统后遗症中潜在使用TSPO配体开辟了一条新途径。与对照组相比，动物在所有任务中均表现出认知能力下降，并且这种损伤至少可以通过激活神经胶质介导的免疫反应和上调TSPO来部分介导。结论TSPO-PET可能被用作小胶质细胞活化和脑膜炎后长期认知障碍的影像学生物标志物。此外，这项研究为感染诱导的神经系统后遗症潜在使用TSPO配体开辟了一条新途径。与对照组相比，动物在所有任务中均表现出认知能力下降，并且这种损伤至少可以通过激活神经胶质介导的免疫反应和上调TSPO来部分介导。结论TSPO-PET可能被用作小胶质细胞活化和脑膜炎后长期认知障碍的影像学生物标志物。此外，这项研究为感染诱导的神经系统后遗症潜在使用TSPO配体开辟了一条新途径。