title: Activation of the Protein Kinase B (Akt) Reduces Nur77-induced Apoptosis During Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rat.
abstract: Nur77 is a potent pro-apoptotic member of the orphan nuclear receptor superfamily. Our previous study revealed Nur77-mediated apoptosis is also involved in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). Previous researches show that Protein Kinase B (Akt) negatively regulates Nur77 DNA binding and apoptosis by phosphorylating Nur77. To determine whether activation of Akt is directly associated with Nur77 dependent apoptosis pathway, we hypothesized that insulin, an activator of Akt, may effectively ameliorate EBI by inhibiting Nur77 transcriptional activity. This study was designed to explore the neuroprotective effects of insulin in EBI after SAH. Adult male Sprague Dawley (SD) rats were randomly assigned to three groups: control, SAH, and SAH + insulin. 0.2 U/kg insulin was administered subcutaneous, starting 30 min after the SAH induced, 3 times/d. Insulin significantly activated Akt, increased the phosphorylation of Nur77 and alleviated increases in Bcl-2 and cyto C associated with SAH induction. Improvement of neurological deficit, alleviation of brain edema, and amelioration of EBI were obtained after treatment of insulin. TUNEL-positive cells were reduced markedly in brain cortex by insulin. Our studies indicate activation of Akt plays important roles in inhibiting the Nur77-dependent apoptotic pathway. These findings strongly support the hypothesis that insulin treatment can ameliorate EBI after experimentally induced SAH.
authors.affiliation: Department of Neurosurgery, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Neurosurgery, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China shijixinnj@hotmail.com.
authors.forename: Jixin
authors.initials: J
authors.lastname: Shi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D013702:Temporal Lobe / Q000187:drug effects / Q000473:pathology
chemical_list: D007328:Insulin; D018696:Neuroprotective Agents; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D051057:Proto-Oncogene Proteins c-akt