Synergistic neuroprotection of total flavonoids and lignans from Valeriana amurensis on AD rat model

• First discovery that flavonoids from V. amurensis have inhibitory effects on the expression of efflux transporter p-glycoprotein in blood-brain barrier. • The mechanism of synergistic anti AD effect of V. amurensis flavonoids and lignans was elucidated for the first time. • The mechanism of neuroprotective effects of V. amurensis lignans on brain neurons was elucidated as inhibiting inflammatory response in glial cells and reducing neuronal dendritic spine damage. The purpose of this study was to elucidate the synergistic neuroprotection of total flavonoids and lignans from V. amurensis . The effect of total flavonoids on the expression of p-glycoprotein (P-gp) in blood-brain barrier (BBB) was investigated using normal rats. To further investigate the synergistic neuroprotection of total flavonoids and lignans, the effects of mixture of total flavonoids and lignans from V. amurensis (MTFL-V) on the cognitive function and histopathological damages were evaluated with Alzheimer's disease (AD) rat model induced by Aβ 1-42 . The synergistic neuroprotective mechanism of total flavonoids and lignans was demonstrated by treatment effects of combination of total lignans with P-gp inhibitor Verapamil on AD rats. As a result, total flavonoids significantly inhibited the expression level of the P-gp in BBB of normal rats. The MTFL-V significantly improved the learning and memory abilities, and reducing the neuronal damage of Aβ 1-42 induced AD rats. Compared to treated with total lignans alone, treated with combination of total lignans with P-gp inhibitor Verapamil showed more significant reduction in neuronal damage in AD rats. Moreover, the total lignans reduced the release of inflammatory factors such as IL-6, IL-1β, TNF-α, and iNOS, which are associated with glial cell proliferation in AD rats, inhibiting overactivation of Fyn and CaMKIIα, along with increasing the expression ratio of p-ERK and ERK1/2. Consequently, the flavonoids and lignans from V. amurensis have synergistic neuroprotective effects in AD rats. The mechanism is that the flavonoids promote the lignans to pass through the BBB into brain by inhibiting the expression of P-gp in BBB, thereby the total lignans exerts neuroprotection by inhibiting Aβ 1-42 induced inflammatory response in glial cells and neuronal dendritic spine damage in AD rats.