Euonymus alatus is considered to elicit various beneficial effects against cancer, hyperglycemia, menstrual discomfort, diabetic complications, and detoxification. The young leaves of this plant are exploited as food and also utilized for traditional medicine in East Asian countries, including Korea and China. Our preliminary study demonstrated that ethanolic extract from the Euonymus alatus leaf (EAE) exhibited the strongest antioxidant enzyme-inducing activity among more than 100 kinds of edible tree leaf extracts. This study investigated whether EAE could attenuate the cognitive deficits caused by oxidative stress in mice. Oral intubation of EAE at 100 mg/kg bw or higher resulted in significant improvements to the memory and behavioral impairment induced via i.p. injection of scopolamine. Furthermore, EAE enhanced the expression levels of hippocampal neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor in mice, activated the Nrf2, and the downstream heme oxygenase-1 (HO-1) a quintessential antioxidant enzyme. As rutin (quercetin-3-O-rutinose) was abundantly present in EAE and free quercetin was able to induce defensive antioxidant enzymes in an Nrf2-dependent manner, our findings suggested that quercetin derived from rutin via the intestinal microflora played a significant role in the protection of the mouse hippocampus from scopolamine-induced damage through BDNF-mediated Nrf2 activation, thereby dampening cognitive decline.

Our previous in vitro study demonstrated that the ethanol extract from young leaves of Euonymus alatus (so‐called burning bush spindle tree) had antioxidant and neuroprotective activities. In the present study, we examined whether oral supplementation of the extract recovers learning and memory capabilities in a scopolamine‐induced acute hypomnesic mouse model. Behavioral tests showed that spatial learning and memory were improved by the extract treatment in scopolamine‐treated mice. Histological damage observed in the hippocampal region of the scopolamine‐treated mouse brain was attenuated by oral administration of the extract. Oxidative stress markers, including plasma 8‐hydroxy‐2′‐deoxyguanosine and hepatic malondialdehyde increased in scopolamine‐injected mice were decreased by the extract treatment. The expression levels of antioxidant proteins such as heme oxygenase‐1 and nuclear factor (erythroid‐derived 2)‐like 2 in the hippocampal tissue homogenates were decreased in group treated with scopolamine alone while the expression of those proteins was restored by the extract treatment. In addition, synaptic plasticity biomarkers such as neurotrophic factors, including postsynaptic density protein‐95, brain‐derived neurotrophic factor and N‐methyl‐D‐aspartate receptor, were enhanced in the extract‐treated mouse hippocampal tissue compared to the group exposed to scopolamine alone. These findings indicate that Euonymus alatus leaf extract could rescue learning and memory impairment caused by oxidative stress‐dependent hippocampal damage through upregulated antioxidant response and strengthened synaptic function of neuronal circuits particularly in the hippocampus. Support or Funding Information This study was funded by the Forest Resources Development Institute of Gyeongsanbuk‐do, Andong, Republic of Korea.