The Nrf-1 and Nrf-2 transcription factors play a pivotal role in the cellular defence against the toxic effects of reactive oxygen species (ROS). Although ROS are key effectors of neuronal death after ischaemic and traumatic brain injury, it is not known whether Nrf-1 and Nrf-2 are involved in neuroprotective signalling. Here, we analysed the temporal and spatial expression pattern of Nrf-1 and Nrf-2 after unilateral excitotoxic lesion of mouse hippocampus. In marked contrast to previous in vitro studies, where upregulation of these transcription factors on the mRNA level was never detected, we found a strong induction of Nrf-1 mRNA and protein expression in neurons of the lesioned hippocampus, accompanied by a weak elevation of Nrf-2 mRNA levels. Nrf-1 predominantly localized to the nucleus in the injured hippocampus. Furthermore, expression of the cytoprotective enzyme, heme oxygenase-1, a major target of Nrf-1 and Nrf-2 action, was coregulated with Nrf-1 in the same hippocampal neurons, suggesting that Nrf-1 is functionally active. Because Nrf-1 and Nrf-2 are potent inducers of various cytoprotective proteins, our data suggest a role of Nrf-1 and Nrf-2 in neuronal survival after acute brain injury.