Heparin-binding epidermal growth factor-like growth factor in hippocampus:Modulation of expression by seizures and anti-excitotoxic action

The expression of heparin-binding epidermal growth factor-like growth facto r (HB-EGF), an EGF receptor ligand, was investigated in rat forebrain under basal conditions and after kainate-induced excitotoxic seizures. In additi on, a potential neuroprotective role for HB-EGF was assessed in hippocampal cultures. In situ hybridization analysis of HB-EGF mRNA in developing rat hippocampus revealed its expression in all principle cell layers of hippoca mpus from birth to postnatal day (P) 7, whereas from P14 through adulthood, expression decreased in the pyramidal cell layer versus the dentate gyrus granule cells. After kainate-induced excitotoxic seizures, levels of HB-EGF mRNA increased markedly in the hippocampus, as well as in several other co rtical and limbic forebrain regions. In the hippocampus, HB-EGF mRNA expres sion increased within 3 hr after kainate treatment, continued to increase u ntil 24 hr, and then decreased; increases occurred in the dentate gyrus gra nule cells, in the molecular layer of the dentate gyrus, and in and around hippocampal pyramidal CA3 and CA1 neurons. At 48 hr after kainate treatment , HB-EGF mRNA remained elevated in vulnerable brain regions of the hippocam pus and amygdaloid complex. Western blot analysis revealed increased levels of HB-EGF protein in the hippocampus after kainate administration, with a peak at 24 hr. Pretreatment of embryonic hippocampal cell cultures with HB- EGF protected neurons against kainate toxicity. The kainate-induced elevati on of [Ca2+](i) in hippocampal neurons was not altered in cultures pretreat ed with HB-EGF, suggesting an excitoprotective mechanism different from tha t of previously characterized excitoprotective growth factors. Taken togeth er, these results suggest that HB-EGF may function as an endogenous neuropr otective agent after seizure-induced neural activity/injury.