| Flavonoids belong to a family of polyphenolic compounds, which are widely found in a variety of fruits, vegetables, tea and wine. More importantly, flavonoids are served as one type of the active ingredients in traditional Chinese medicines. Different lines of evidence support that flavonoids have impacts in many aspects of human health, including anti-tumor, anti-oxidation and anti-inflammation. Recently, numerous attentions have been focused on the neuronal beneficial effects of flavonoids, including the neuroprotection against neurotoxin stress, as well as the promotion of memory, learning and cognitive functions. Previous studies in cultured cortical neurons and PC12 cells showed that flavonoids possessed the abilities of anti-oxidation and inhibiting the Abeta-induced cytotoxicity. These properties made the flavonoids to be the potential candidates for drug development for Alzheimer's disease. In this study, the bioactivities of flavonoids were screened and determined in nervous system. Specifically, the induction of neurite outgrowth, the modulation of synapse formation, and the promotion on the synthesis and secretion of neurotrophic factors were further revealed in neuron and astrocyte.;After screening of 65 flavonoids, 20 flavonoids were found to up regulate the protein levels of neurofilaments, which are the main protein markers for neurite outgrowth. Amongst the 20 flavonoids, sulphureting, luteolin, daidzin, genistein, genistin, hyperin and isorhamnetin could increase the protein levels of neurofilaments for over 3 folds. The flavonol aglycone, isorhamnetin, was found to have the most promising effect in up regulating the expression of neurofilaments. In addition to this neuronal differentiation effect, the application of isorhamnetin in cultured PC12 cells could potentiate the effect of nerve growth factor (NGF) in promoting neurite outgrowth. For mechanistic delineation, it was found that isorhamnetin alone could not activate the NGF-induced signaling pathway, and which could not potentiate the effect of NGF in activating the downstream signaling molecules. For the modulation of synapse formation, the flavonoids, (-)-catechin, luteolin and isorhamnetin, were found to stimulate the expressions of synaptic proteins including synaptotagmin, synapsin II, synaptosomal-associated protein 25 and post-synaptic density protein 95 in cultured cortical and hippocampal neurons. But none of these flavonoids could stimulate the release of neurotransmitters including glutamate and gamma-aminobutyric acid. For the regulation of neurotrophic factors, calycosin, isorhamnetin, luteolin and genistein, were found to be highly effective in inducing the synthesis and secretion of the neurotrophic factors, i.e. NGF, glial cell-derived neurotrophic factor and brain-derived neurotrophic factor. For the molecular mechanism, it was demonstrated that the flavonoid-induced signaling responses were similar to that of estrogen receptor-dependent signaling pathway.;Here, different flavonoids were found to possess neuronal beneficial effects in different aspects. Some flavonoids, including isorhamnetin, luteolin and genistein, were found to be effective in the studies of neurite outgrowth, synaptogenesis, and neurotrophic factor expressions, as described above. This supported the multi-functional properties of flavonoids. In clinical studies, flavonoids have been used for promoting memory and cognition functions in aging and neurological disorders. Indeed, the present study fully explained these phenomena both in cellular and molecular levels. More importantly, these flavonoids might be considered as the good candidates in developing potential drugs, or health food supplements, in treating, or preventing different neurological disorders. |
