The accumulation of amyloid-beta (A beta) and oxidative stress damage in the brain are recognized as early features of Alzheimer's disease (AD). The cocaine- and amphetamine-regulated transcript (CART) peptide may possibly play an antioxidative role in neurons. The aim of this study was to investigate the potential antioxidant mechanism of CART peptide in a rat model of AD. We microinjected of A beta(1-42) (2 mu l/4 mu g/hemisphere) into rat hippocampus to set a rat model of AD. A pre-microinjection of CART peptide (1 mu l/0.02 mu g/hemisphere) into rat hippocampus was administered for five consecutive days before A beta(1-42) treatment. We found that A beta(1-42) microinjection led to reduction of endogenous CART level in rat hippocampus. CART pretreatment improved the spatial memory and locomotor ability of AD rats. CART peptide decreased the A beta(1-42) and A beta production-associated enzyme BACE1 levels. Moreover, CART peptide attenuated the oxidative stress damage with a concrete manifestation of increased MDA as well as decreased T-SOD, GSH and ATP levels in the hippocampus of A beta(1-42)-treated rat, which may be causatively implicated the activating of Nrf2/HO-1 signaling pathway. Furthermore, CART peptide attenuated neuronal apoptosis with decreased Bax, caspase-9 and caspase-3 levels and increased Bcl-2 level in rat hippocampus. Our results therefore indicate that CART peptide could serve as an antioxidant in early therapy for AD. (C) 2018 Elsevier Inc. All rights reserved.