Cell death and associated c-jun induction in perinatal hypoxia-ischemia. Effect of the neuroprotective drug dexamethasone.
Previous studies in a model of unilateral hypoxia-ischemia in the developing rat brain have shown induction of the mRNAs of c-fos and c-jun and presence of apoptotic DNA fragmentation. In this same model, dexamethasone confers neuroprotection if given before the insult. Since c-fos and c-jun have been involved in several models of cell death, we investigated whether the neuroprotective effect of dexamethasone could be associated with changes in expression of these genes. Rat pups, pre-treated with either 0.5 mg/kg dexamethasone or vehicle 48 h, 24 h and immediately before the injury, were subjected to ligation of the left common carotid artery followed by 3 h hypoxia. Analysis of c-fos and c-jun expression at 2 h, by means of in situ hybridization, revealed diminished induction in dexamethasone-treated animals. Jun immunoreactivity, but not Fos, and DNA fragmentation, assessed by in situ end-labeling of fragmented DNA, were present at 24 h only in vehicle-injected animals. Electrophoresis of brain extracted DNA revealed a ladder pattern in all the animals. Our results show a relationship between Jun overexpression and cell-death in the hypoxic-ischemic developing brain and suggest that dexamethasone exerts its protective effect anteceding immediate early gene induction, at some early point in post-ischemic signal transduction.
Macaya
A
A
Biochemistry and Molecular Biology Research Center, Vall d'Hebron Hospital, Barcelona, Spain.
Munell
F
F
Ferrer
I
I
de Torres
C
C
Reventós
J
J
D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D003907:Dexamethasone