Background: Aucubin (Au) has anti-oxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in a H 2 O 2 -induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model.Methods: Neuronal apoptosis, brain water content, histological damages and neurological deficits and cognitive functions were measured. We performed western blot, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry and enzyme linked immunosorbent assay (ELISA). RNA interference experiments were performed to determine the effects of Nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with intraperitoneal injection of Au.Results: We found that Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS) and reduced cell apoptosis in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1(HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au.Conclusions: Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system. pathobiological features of secondary brain damage [4,5]. Excessive production of free radicals leads to lipid peroxidation, protein degradation, and genotoxicity leading to cellular and tissue damage [6].The brain is an organ with a high content of polyunsaturated fatty acids, which also makes it vulnerable to free radical attack and lipid peroxidation [7]. In addition, OS damage to mitochondrial function can collapse the cellular bioenergetics leading to cell apoptosis [6]. These OS-induced damaged cells releases damage associated molecular patterns (DAMPs; e.g. ATP, RNA, high mobility group box-1) to initiate or exacerbate neuroinflammation, which can also further promote ROS generation [8,9]. Extensive animal data suggest that elevated antioxidant response and reduced inflammation would attenuate brain damage [10][11][12].Nuclear factor erythroid-2 related factor 2 (Nrf2) has considerable neuroprotective effects in central nervous system (CNS) diseases[13-15]. Nrf2 is a transcription factor that takes part in regulation of cellular response to oxidative stress. Under normal physiological conditions, Kelch-like ECH-associated protein 1 (Keap1) combines with Nrf2 and enhances Nrf2 degradation. Once stimulated, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE) in the promoter of antioxidant genes, thereby inducing the expression of antioxidant and detoxifi...