Role of microglial Nrf2 activation in preventing neuronal death Caused by microglial hyperactivation is investigated by using BV-2 microglial cells as modulator and primary neurons as target. Pretreatment of microglial cells with tBHQ, a phenolic antioxidant activating Nrf2. attenuated the LPS-derived overproduction of pro-inflammatory neurotoxic mediators like TNF-alpha, IL-1 beta, IL-6, PGE(2), and NO as well as the morphological changes associated with microglial hyperactivation. Pretreatment of BV-2 cells with tBHQ suppressed LPS-induced phosphorylation of p38 required for overproduction of neurotoxic mediators. Results obtained using Nrf2-specific shRNA showed that expression of Nrf2 in microglia plays a critical role in tBHQ-derived suppression of LPS-induced p38 phosphorylation and microglial hyperactivation. Conditioned Culture media taken from LPS-stimulated microglia cause neuronal death. However, the conditioned media taken from tBHQ-pretreated and LPS-stimulated microglia did not Cause death of primary neurons. This Suggested that prior activation of Nrf2 in microglia may inhibit microglial hyperactivation and prevent neuronal death. (C) 2009 Elsevier Inc. All rights reserved.