Suffruticosol B from Paeonia lactiflora Ameliorates Alzheimer's Disease Pathology by Inhibiting MAO‐B Activity

ABSTRACT Monoamine oxidase B (MAO‐B) has emerged as a therapeutic target for Alzheimer's disease (AD) due to its involvement in the synthesis of γ‐aminobutyric acid (GABA) in reactive astrocytes, which inhibits neuronal activity. Suffruticosol B (Suf‐B), isolated from Paeonia lactiflora , is one of the resveratrol oligomers. Although resveratrol oligomers have demonstrated neuroprotective effects, it remains unexplored whether Suf‐B exerts therapeutic effects on AD by targeting MAO‐B. In this study, we investigated whether Suf‐B alleviates AD pathology by mitigating reactive astrogliosis and inhibiting the overproduction of astrocytic GABA. After confirming the MAO‐B inhibitory effect of Suf‐B through MAO‐B enzyme assay, we administered Suf‐B to APP/PS1 AD model mice. To test the potential therapeutic action of Suf‐B in AD, a series of experiments were conducted, including behavioral tests such as the open field test, novel object recognition test, Barnes maze test, passive avoidance test, as well as immunohistochemistry and whole‐cell patch‐clamp recordings. We found that Suf‐B markedly inhibited MAO‐B activity without causing cytotoxicity. Immunohistochemistry and electrophysiology experiments demonstrated that Suf‐B significantly reduced astrocyte reactivity, as well as an aberrant increase in GABA production and tonic GABA release from astrocytes in AD. Behavior test results indicated that Suf‐B treatment restored cognitive function in APP/PS1 mice. In conclusion, Suf‐B effectively reduces excessive GABA production in reactive astrocytes by inhibiting MAO‐B, normalizing aberrant inhibition in hippocampal neurons in an AD mouse model. These results suggest that Suf‐B has potential as a treatment for AD and may be applicable to other brain diseases associated with reactive astrogliosis.