Luteolin (3',4',5,7-tetrahydroxyflavone), a flavonoid commonly found in vegetables, has been shown to possess neurotrophic properties, but the underlying mechanism remains unclear. We hypothesize that luteolin could potentiate the neurotrophic activities of nerve growth factor (NGF) by interacting with it. The binding of luteolin with NGF was confirmed by an ultra-filtration assay and Biacore analysis. In cultured rat pheochromocytoma PC12 cells, the combination of low-dose luteolin and NGF was able to enhance the NGF-induced differentiation and to increase the expression of neurofilaments. Furthermore, this co-treatment induced the phosphorylation of the tropomyosin-related kinase A receptor (TrkA) and its downstream signaling pathways. Notably, the combinational effects were blocked...[ Read more ]

Luteolin (3',4',5,7-tetrahydroxyflavone), a flavonoid commonly found in vegetables, has been shown to possess neurotrophic properties, but the underlying mechanism remains unclear. We hypothesize that luteolin could potentiate the neurotrophic activities of nerve growth factor (NGF) by interacting with it. The binding of luteolin with NGF was confirmed by an ultra-filtration assay and Biacore analysis. In cultured rat pheochromocytoma PC12 cells, the combination of low-dose luteolin and NGF was able to enhance the NGF-induced differentiation and to increase the expression of neurofilaments. Furthermore, this co-treatment induced the phosphorylation of the tropomyosin-related kinase A receptor (TrkA) and its downstream signaling pathways. Notably, the combinational effects were blocked by the Trk inhibitor, indicating that the potentiation should be specifically mediated via TrkA. In parallel, apigenin (4',5,7- trihydroxyflavone), an analog of luteolin, was validated to bind with another neurotrophin, brain-derived neurotrophic factor (BDNF). The combination of apigenin and BDNF significantly potentiated the BDNF-induced neurogenesis and synaptogenesis in cultured rat neurons. Additionally, apigenin and BDNF were found to work synergistically in reducing amyloid-beta (Aβ)-induced cytotoxicity and mitochondrial dysfunction. Overall, these findings suggest the potential of dietary flavonoids, e.g., apigenin and luteolin, in treating health problems related to the deficiency of neurotrophins.

Mitochondrial hormesis is proposed here as another explanation for the neurotrophic mechanism of luteolin. In cultured PC12 cells, low concentrations of luteolin caused a mild and reversible loss of mitochondrial membrane potential (MMP), while high concentrations led to intense and sustained depolarization of MMP. The disturbance in MMP was shown to be closely linked to the trophic and/or toxic effects induced by luteolin; because common mitochondrial uncouplers also exhibit a similar bi-phasic dose-response on cell viability as that of luteolin. Along with the induced MMP disruption, luteolin triggered the development of autophagy and mitophagy. Subsequent application of autophagy inhibitors blocked the neurotrophic activities, as induced by luteolin, and sensitized the cells to be less resistant to the cytotoxicity of luteolin. Besides luteolin, the hormetic property of other flavonoids could also be identified in cultures. Overall, this study provides a mechanistic explanation for the neuro-beneficial effects of luteolin and its related flavonoids, which serve as hormetic pharmacological inducers that could stimulate cells to become more robust and adapt to threats.

Peanut (Arachis hypogaea L.) shell is an agricultural waste that needs to be recycled. The ethanolic extract of peanut shell, named as PSE, is enriched with luteolin and has the potential to act as a neurotrophic agent. The application of PSE to cultured PC12 cells, SH-SY5Y cells, and rat neurons increased the proportion of differentiated cells. Concomitantly, the neuronal differentiation markers, i.e., neurofilaments, were increased in the cultures treated with PSE. The therapeutic application of PSE was further assessed in mice with chronic unpredictable mild stress-induced depression. The administration of PSE was found to enhance sucrose water consumption in depressive mice, while reducing immobile time in both tail suspension and forced swimming tests. These effects were accompanied by increased levels of neurotrophic factors and neurotransmitters, as well as decreased levels of stress hormones, indicating the anti-depressive effect of PSE. In addition, PSE treatment mitigated the levels of inflammatory mediators in the brain, serum, and small intestine. The expression of tight junction proteins in the gut was elevated, which coincided with an increase in the abundance and diversity of gut microbiota upon PSE treatment. These findings suggest that PSE having a high amount of luteolin has the potential to be developed as a dietary supplement to promote brain health.