THESIS
2023
1 online resource (xxii, 211 pages) : illustrations (some color)
Abstract
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...[
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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.
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