Heparin-binding epidermal growth factor-like growth factor mRNA expression in neonatal rat brain with hypoxic/ischemic injury.

The neuronal expression of mRNA of heparin-binding epidermal growth factor-like growth factor (HB-EGF) was investigated in immature rat brains. Two rat models were used in this study. One was a hypoxic/ischemic (HI) brain injury model, and the other was an N-methyl-d-aspartate (NMDA) intracerebral injection model. The former model was made by permanent ligation of the left carotid artery and subsequent exposure to 2 h of hypoxia. After the HI insult, the HB-EGF mRNA was assessed by a Northern blot analysis. The levels of transcripts for HB-EGF in the cerebral cortex and the hippocampus of the ligated side were significantly higher than those of non-treated rats from 3 to 24 h after the insult. The spatial distribution of the mRNA of HB-EGF was also studied using in situ hybridization. Three to 24 h after the hypoxia, hybridization signals were intense in neuronal cytoplasm on the ligated side, but a focally decreased signal was seen in infarcted areas. Strongly increased mRNA expression was observed in the neurons surrounding the infarct. These results indicate that a neonatal HI insult induces a neuronal upregulation of HB-EGF immediately after hypoxia. In the latter model, the intracerebral NMDA injection also induced an immediate, strong upregulation of HB-EGF transcripts. Our results indicate that HB-EGF may act as a neuroprotective factor in the immature brain with HI injury by modulating the neurotoxic process which is mediated by overactivation of the NMDA receptor.