Thymoquinone (TQ) is the main constituent of the oil extracted from Nigella sativa seeds, which is known to be the active constituent responsible for many of the seed antioxidant and anti-inflammatory effects. The present study was designed to investigate whether TQ can protect against Alzheimer's amyloid-beta peptide (A beta) induced neurotoxicity in rat primary neurons. Cultured hippocampal and cortical neurons were treated with A beta(1-42) and TQ simultaneously for 72 h. Treatment with TQ efficiently attenuated A beta(1-42)-induced neurotoxicity, as evidenced by improved cell viability. TQ also inhibited the mitochondrial membrane potential depolarization and reactive oxygen species generation caused by A beta(1-42). In addition, TQ restored synaptic vesicle recycling inhibition, partially reversed the loss of spontaneous firing activity, and inhibited A beta(1-42) aggregation in vitro. These beneficial effects may contribute to the protection against A beta-induced neurotoxicity. In conclusion, our results suggested that TQ has neuroprotection potential against A beta(1-42) in rat hippocampal and cortical neurons and thus may be a promising candidate for Alzheimer disease treatment. (C) 2013 Elsevier Inc. All rights reserved.