Wolf S, Hainz N, Beckmann A, Maack C, Menger M D, Tschernig T, Meier C
Department of Anatomy and Cell Biology, Saarland University, Germany.
Department of Cardiology, Saarland University, Germany.
Brain Res. 2016 Nov 1;1650:224-231. doi: 10.1016/j.brainres.2016.09.013. Epub 2016 Sep 13.
Perinatal hypoxia is a critical complication during delivery and is mostly studied in animal models of postnatal hypoxic-ischemic brain injury. We here studied the effects of postnatal hypoxic-ischemic brain injury in two different sub-strains of C57BL/6 mice, i.e. C57BL/6J and C57BL/6N mice. These two sub-strains show different metabolic properties, for instance an impaired glucose tolerance in C57BL/6J mice. Genetically, this was linked to differences in their nicotinamide nucleotide transhydrogenase (Nnt) genes: In C57BL/6J mice, exons 7-11 of the Nnt gene are deleted, resulting in the absence of functional Nnt protein. The mitochondrial Nnt-protein is one of several enzymes that catalyses the generation of NADPH, which in turn is important for the elimination of reactive oxygen species (ROS). As ROS is thought to contribute to the pathophysiology of hypoxia-ischemia, the lack of Nnt might indirectly increase ROS levels and therefore result in increased brain damage. We therefore hypothesize that lesion score and lesion size will increase in C57BL/6J mice as compared to C57BL/6N mice. Surprisingly, the results showed exactly the opposite: C57BL/6J mice showed a decrease in lesion score and size, associated with a reduced number of apoptotic cells and activated microglia. In contrast, the number of cells with ROS-induced DNA modifications (detected by 8OHdG) was higher in C57BL/6J than C57BL/6N mice. In conclusion, C57BL/6J mice showed reduced ischemic consequences after postnatal hypoxic-ischemic brain injury compared to C57BL/6N mice, with the exception of the amount of ROS-induced DNA-damage. These differences might relate to the lack of Nnt, but also to a modified metabolic setting (cardiovascular parameters, oxygen and glucose metabolism, immune function) in C57BL/6J mice.
围产期缺氧是分娩期间的一种关键并发症，目前大多在产后缺氧缺血性脑损伤的动物模型中进行研究。我们在此研究了产后缺氧缺血性脑损伤对两种不同亚系的C57BL/6小鼠，即C57BL/6J和C57BL/6N小鼠的影响。这两个亚系表现出不同的代谢特性，例如C57BL/6J小鼠存在葡萄糖耐量受损的情况。从基因角度来看，这与它们烟酰胺核苷酸转氢酶（Nnt）基因的差异有关：在C57BL/6J小鼠中，Nnt基因的外显子7至11缺失，导致功能性Nnt蛋白缺失。线粒体Nnt蛋白是催化生成NADPH的几种酶之一，而NADPH对于清除活性氧（ROS）至关重要。由于ROS被认为与缺氧缺血的病理生理学有关，Nnt的缺失可能间接增加ROS水平，从而导致脑损伤加重。因此，我们推测与C57BL/6N小鼠相比，C57BL/6J小鼠的损伤评分和损伤大小会增加。令人惊讶的是，结果却恰恰相反：C57BL/6J小鼠的损伤评分和大小降低，同时凋亡细胞数量和活化小胶质细胞数量减少。相比之下，C57BL/6J小鼠中由ROS诱导的DNA修饰（通过8-羟基脱氧鸟苷检测）的细胞数量高于C57BL/6N小鼠。总之，与C57BL/6N小鼠相比，C57BL/6J小鼠在产后缺氧缺血性脑损伤后缺血后果减轻，但ROS诱导的DNA损伤量除外。这些差异可能与Nnt的缺失有关，也可能与C57BL/6J小鼠中改变的代谢环境（心血管参数、氧和葡萄糖代谢、免疫功能）有关。
