We recently demonstrated that Nrf2, a transcription factor and master regulator of Phase II antioxidant defences, has a key role in neuronal ischemic preconditioning in vitro. Neuronal protection originated from astrocytes not neurons, as no Nrf2 activation occurred in pure neuronal cultures. We currently aim to determine whether the Nrf2 pathway is indeed paradoxically inactive in neurons. Specific overexpression of Nrf2 in vitro in neurons affords significant protection from ischemia and upregulates Nrf2 target products, suggesting the pathway can functionally respond when Nrf2 is present. Basal Nrf2 mRNA expression levels are significantly higher in astrocytes than in neurons in vitro, and Bach-2 a major repressor of Nrf2 activity is significantly increased in neurons, possibly suggesting that the inactivity within neurons stems from a decreased availability of Nrf2, as opposed to impaired downstream pathway function. ChIP experiments reveal a significantly lower association of acetylated histone H3 (a marker of transcriptional activity) at the Nrf2 promoter in neurons versus astrocytes in culture. Application of histone deacetylase inhibitor TSA increases the association of acetylated histone H3 at the Nrf2 promoter in neurons and boosts neuronal Nrf2 mRNA expression. Fluorescent assisted cell sorting of mouse cortical tissue is currently underway to determine whether Nrf2 levels also differ in adult cell populations in vivo. Given that oxidative stress is a key pathological feature of numerous neurodegenerative diseases and stroke, an improved understanding of Nrf2 regulation in neurons is relevant.