title: Treatment with an activator of hypoxia-inducible factor 1, DMOG provides neuroprotection after traumatic brain injury.
abstract: Traumatic brain injury (TBI) is one of the major cause of morbidity and mortality and it affects more than 1.7 million people in the USA. A couple of regenerative pathways including activation of hypoxia-inducible transcription factor 1 alpha (HIF-1α) are initiated to reduce cellular damage following TBI; however endogenous activation of these pathways is not enough to provide neuroprotection after TBI. Thus we aimed to see whether sustained activation of HIF-1α can provide neuroprotection and neurorepair following TBI. We found that chronic treatment with dimethyloxaloylglycine (DMOG) markedly increases the expression level of HIF-1α and mRNA levels of its downstream proteins such as Vascular endothelial growth factor (VEGF), Phosphoinositide-dependent kinase-1 and 4 (PDK1, PDK4) and Erythropoietin (EPO). Treatment of DMOG activates a major cell survival protein kinase Akt and reduces both cell death and lesion volume following TBI. Moreover, administration of DMOG augments cluster of differentiation 31 (CD31) staining in pericontusional cortex after TBI, which suggests that DMOG stimulates angiogenesis after TBI. Treatment with DMOG also improves both memory and motor functions after TBI. Taken together our results suggest that sustained activation of HIF-1α provides significant neuroprotection following TBI.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Augusta University, United States; Department of Veterinary Biosciences & Diagnostic Imaging, College of Veterinary Medicine, The University of Georgia, United States.
authors.forename: Tanusree
authors.initials: T
authors.lastname: Sen
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Augusta University, United States. Electronic address: nsen@gru.edu.
authors.forename: Nilkantha
authors.initials: N
authors.lastname: Sen
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000600:Amino Acids, Dicarboxylic; D043925:Angiogenesis Inducing Agents; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D018697:Nootropic Agents; C000631433:Pdk1 protein, mouse; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D004921:Erythropoietin; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C040947:oxalylglycine
keywords: Angiogenesis; Cell death; DMOG; HIF-1α; Lesion volume; Traumatic brain injury