Gastrodin improves learning and memory in sleep-deprived mice through suppression of ferroptosis in hippocampal neurons via Nrf2

Sleep deprivation (SD) causes various neurological deficits, including impaired learning and memory. Gastrodia elata (G. elata) is a traditional Chinese medicinal herb known for its effects in calming liver yang, dispelling winds, unblocking meridians, and relieving convulsions. It is commonly used to treat neurological disorders. Gastrodin (GAS), the main active component extracted from G. elata, exhibits pharmacological effects, such as antioxidant activity, neuroprotection, and enhancement of cognitive function. This study sought to investigate how GAS affects ferroptosis in the hippocampal neurons of mice with SD and to clarify the underlying mechanism of action. The Morris water maze (MWM) was used to evaluate learning and memory. Specialized assay kits were used to measure the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and lactate dehydrogenase (LDH). Hippocampal neuronal damage was observed using Nissl staining. In both the hippocampus of mice with SD and in HT-22 cells, ferroptosis was investigated using techniques such as Western blot analysis, flow cytometry, and transmission electron microscopy (TEM). GAS alleviated learning and memory deficits in SD mice and protected hippocampal neurons and mitochondria from damage. Western blot analysis revealed that GAS inhibited the abnormal expression of proteins relating to synaptic transmission, oxidative stress, and ferroptosis. Furthermore, the addition of the Nrf2 inhibitor ML385 abolished the effects of GAS on erastin-treated HT-22 cells. These observations indicate that GAS prevents learning and memory impairment in mice with SD by inhibiting hippocampal ferroptosis via Nrf2.