IMMEDIATE-EARLY GENE INDUCTION AFTER NEONATAL HYPOXIA-ISCHEMIA

Immediate early gene (IEG) products, such as FOS and JUN, may partiall y mediate the long-term transcriptional response of CNS cells to speci fic changes in their environment. To determine whether IEG products mi ght be involved in the immature brain's response to hypoxia-ischemia ( H-1), 7-day-old rat pups were subjected to unilateral common carotid a rtery ligation followed by 3 h of hypoxia (8% O2/92% N2) at 37-degrees -C, which results in pathological changes only in specific regions of the hemisphere ipsilateral to ligation 49 . Time course experiments we re performed, in which animals were sacrificed between 1 and 24 h afte r H-1. RNAs from several brain regions were analyzed by Northern blot hybridization for their relative concentrations of nine IEG mRNAs (c-f os, c-jun, junB, TIS 1 (nur77), TIS7, TIS8 (zif268), TIS10, TIS11, and TIS21). Induction of all IEGs, except TIS7 and TIS10, was observed in ipsilateral forebrain, and, less frequently, in contralateral forebra in, at 1, 2, and 3 h post-hypoxia. In some animals, lower levels of ex pression were also detected at 4, 18 and 24 h. With minor exceptions, co-induction of all seven IEGs was observed in a given RNA sample. Ind uction of two other mRNAs, representing the heat shock and astrocytic responses, were also observed. Hsp70 mRNA levels were increased only i n the brains of animals exhibiting IEG induction. However, hsp70 induc tion was confined to the ipsilateral forebrain, implying a more direct relationship between its expression and permanent morphological damag e. GFAP MRNA induction occurred predominantly in ipsilateral forebrain samples at 18 and 24 h post-hypoxia. Levels of B-actin and ubiquitin mRNAs were relatively constant in the same RNA samples. In control exp eriments c-fos mRNA induction was not detected after sham ligation wit h hypoxia, ligation with sham hypoxia, or hypoxia alone. These results suggest that the immature brain is highly responsive to H-I at the le vel of gene expression, involving at least three different rapid respo nse systems.