Brain damage resulting from postnatal hypoxic-ischemic brain injury is reduced in C57BL/6J mice as compared to C57BL/6N mice

Abstract 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/6 J and C57BL/6N mice. These two sub-strains show different metabolic properties, for instance an impaired glucose tolerance in C57BL/6 J mice. Genetically, this was linked to differences in their nicotinamide nucleotide transhydrogenase (Nnt) genes: In C57BL/6 J mice, exons 7 to 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/6 J mice as compared to C57BL/6N mice. Surprisingly, the results showed exactly the opposite: C57BL/6 J 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/6 J than C57BL/6N mice. In conclusion, C57BL/6 J 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/6 J mice.