Research Papers: Pathology:
Dichloroacetate treatment improves mitochondrial metabolism and reduces brain injury in neonatal mice
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Yanyan Sun1,2,*, Tao Li1,2,3,*, Cuicui Xie2, Yaodong Zhang2,3, Kai Zhou2,4, Xiaoyang Wang1,5, Klas Blomgren4 and Changlian Zhu1,2,6
1 Department of Pediatrics, Third Affiliated Hospital of Zhengzhou University, Henan, China
2 Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
3 Zhengzhou Children’s Hospital, Zhengzhou, China
4 Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
5 Perinatal Center, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
6 Henan Provincial Key Laboratory of Child Brain Injury, Zhengzhou, China
* These authors have contributed equally to this work
Changlian Zhu, email:
Keywords: apoptosis, autophagy, brain ischemia, mitochondria, pyruvate dehydrogenase, Pathology Section
Received: December 05, 2015 Accepted: April 22, 2016 Published: May 03, 2016
The purpose of this study was to evaluate the effect of dichloroacetate (DCA) treatment for brain injury in neonatal mice after hypoxia ischemia (HI) and the possible molecular mechanisms behind this effect. Postnatal day 9 male mouse pups were subjected to unilateral HI, DCA was injected intraperitoneally immediately after HI, and an additional two doses were administered at 24 h intervals. The pups were sacrificed 72 h after HI. Brain injury, as indicated by infarction volume, was reduced by 54.2% from 10.8 ± 1.9 mm3 in the vehicle-only control group to 5.0 ± 1.0 mm3 in the DCA-treated group at 72 h after HI (p = 0.008). DCA treatment also significantly reduced subcortical white matter injury as indicated by myelin basic protein staining (p = 0.018). Apoptotic cell death in the cortex, as indicated by counting the cells that were positive for apoptosis-inducing factor (p = 0.018) and active caspase-3 (p = 0.021), was significantly reduced after DCA treatment. The pyruvate dehydrogenase activity and the amount of acetyl-CoA in mitochondria was significantly higher after DCA treatment and HI (p = 0.039, p = 0.024). In conclusion, DCA treatment reduced neonatal mouse brain injury after HI, and this appears to be related to the elevated activation of pyruvate dehydrogenase and subsequent increase in mitochondrial metabolism as well as reduced apoptotic cell death.
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