The combination of luteolin and l-theanine improved Alzheimer disease-like symptoms by potentiating hippocampal insulin signaling and decreasing neuroinflammation and norepinephrine degradation in amyloid-β-infused rats.

Luteolin and l-theanine have anti-inflammatory, antioxidant, and possible antidiabetic activities, and they may synergistically protect against dementia. Here, we hypothesized that a combination of luteolin and l-theanine would synergistically act to improve memory function and glucose disturbances in rats infused with amyloid-β, and the mechanisms underlying these actions were investigated. Rats that received an amyloid-β(25-35) infusion into the CA1 region of the hippocampus were fed dextrin (AD-CON), 0.1% luteolin (AD-Lut), 0.2% l-theanine (AD-Thea), or both 0.05% luteolin and 0.1% l-theanine (AD-LuTh) in conjunction with a high-fat diet over 8 weeks. AD-LuTh improved memory function, as determined by water maze and passive avoidance tests, by potentiating the hippocampal insulin signaling and reducing inflammation: Luteolin mainly potentiated insulin signaling via the pAkt➔pGSK➔pTau pathway, and l-theanine primarily reduced tumor necrosis factor-α. In the metabolomics analysis of the hippocampus lysates, the concentration of proline, phenylpyruvic acid, and normetanephrine decreased in the AD-LuTh compared to AD-CON. Norepinephrine contents were lower in the AD-CON than non-AD rats with a high fat diet with 0.2% dextrin, whereas AD-Thea and AD-LuTh inhibited the decrease. Both the AD-Lut and AD-LuTh increased glucose infusion rates and decreased hepatic glucose output under basal and hyperinsulinemic conditions, indicating improved whole-body and hepatic insulin sensitivity. Disturbances in glucose-stimulated insulin secretion during hyperglycemic clamp were most effectively corrected by the AD-Lut and AD-LuTh treatments. In conclusion, the hypothesis of the study was accepted. The combination of luteolin and l-theanine prevented Alzheimer disease-like symptom, possibly by improving hippocampal insulin signaling, norepinephrine metabolisms, and decreasing neuroinflammation. The combination of luteolin and l-theanine may be a useful therapeutic option for preventing and/or delaying the progression of memory dysfunction.