title: Inhibition of c-Jun N-terminal kinase ameliorates early brain injury after subarachnoid hemorrhage through inhibition of a Nur77 dependent apoptosis pathway.
abstract: Nur77 is a potent pro-apoptotic member of the orphan nuclear receptor superfamily. Our previous study revealed Nur77-mediated apoptotic also involved in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). Previous researches show that c-Jun N-terminal kinase (JNK) positively regulates Nur77 nuclear export and apoptosis by phosphorylating Nur77. To determine whether activation of JNK is directly associated with Nur77 dependent apoptosis pathway. We hypothesized that SP600125, a chemical inhibitor of JNK, may effectively ameliorate EBI by inhibiting Nur77 phosphorylation and its transcriptional activity. Hence, in this study was designed to explore the neuroprotective effects of SP600125 in EBI after SAH. Adult male SD rats were randomly assigned to four groups: control; SAH + DMSO; SAH + SP10 and SAH + SP30, a dose of 10 and 30 mg/kg SP600125 was directly administered intraperitoneally 30 min before and 2 h after SAH induction. SP600125 markedly decreased expressions of p-JNK, p-Nur77, Bcl-2, cyto C, caspase-3 and inhibited apoptosis. Improvement of neurological deficit, alleviation of brain edema and amelioration of EBI were obtained after treatment of SP600125. Transferase-mediated dUTP nick end labeling-positive cells were reduced markedly in brain cortex by SP600125. Our studies indicate JNK plays important roles in Nur77 activation. These findings strongly support the hypothesis that SP600125 treatment can ameliorate EBI after experimentally induced SAH by inhibiting a Nur77-dependent apoptotic pathway.
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.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhou
authors.forename: Jixin
authors.initials: J
authors.lastname: Shi
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000873:Anthracenes; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases