The transcription factor, nuclear factor E2 (erythroid-derived 2)-related factor 2 (Nrf2), is essential for the induction of a battery of phase II detoxification genes through the antioxidant response element (ARE) that lies in their promoter region. Genes driven by the ARE are up-regulated in response to various stressors of the cellular environment. These genetic changes to the cellular reducing potential may reflect an intrinsic damage response to harmful toxicants. Analysis of transgenic reporter mice following kainate injection revealed selective ARE activation within the damaged hippocampus. Further, 2 x 2 microarray analyses comparing Nrf2 knockout versus wild-type hippocampi unmasked gene changes associated with ion movement and myelination, in addition to alterations to detoxification-related genes. Nrf2 knockout mice were more sensitive to kainate toxicity, as evidenced by elevated seizure severity, seizure duration, hippocampal neuron damage and mortality. Knockout mice injected with kainate displayed altered glial fibrillary acidic protein immunoreactivity and increased microglial infiltration. The wild-type to knockout damage differential was not dependent on the peripheral metabolism of the excitotoxin, was well correlated with increased seizure susceptibility, and was therefore not necessarily the neuroprotective effects of Nrf2. These results combine to support a role for Nrf2 in the neural cell defense response of the adult brain.