Coeloglossum viride var. bracteatum extract attenuates Aß-induced toxicity by inhibiting RIP1-driven inflammation and necroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Tibetan ginseng named Wangla (tuber of Coeloglossum viride var. bracteatum) is a traditional tonic that has Yang-strengthening and qi-enhancing, tranquilizing, intelligence-enhancing and longevity-enhancing properties. It has been used to treat impotence, spermatorrhea, anemia and insomnia. Therefore, its characteristic components and neuronal modulating effects were studied. AIM OF THE STUDY: To investigate the elimination of Aß-induced toxicity by CE and to elucidate the molecular mechanisms involving BDNF, FGF2, and their related signaling axis, and the RIP1-driven inflammatory pathway. MATERIALS AND METHODS: We established Aß-induced toxicity models in cultured neurons and ICR mice, respectively. MWM and fear conditioning tests were performed for behavioral analysis of cognitive functions in mice. Western blot was used to investigate the levels of BDNF, FGF2, and their downstream effector TrkB/Akt/Bcl-2, as well as the RIP1-driven RIP1/RIP3/MLKL pathway. Immunofluorescence assay is used to examine the status of glial cells. RESULTS: CE abrogated Aß toxicity and inhibited apoptosis in cultured neurons, mainly by regulating the BDNF, FGF2, and TrkB/Akt signaling pathways as well as RIP1-driven inflammation and necroptosis. Similarly, mice injected intracerebrally with Aß exhibited cognitive deficits and had elevated oxidative stress and inflammatory factors detected in their serum and brain. However, CE-treated mice showed recovery of cognitive abilities and quelled levels of oxidative stress and inflammatory factors. Moreover, Aß toxicity led to a reduction in BDNF, FGF2, and related signaling regulators in the hippocampus and prefrontal cortex, accompanied by activation of RIP1-driven inflammatory signaling pathways, and a reduction in TBK1 and Bcl-2. However, CE restored the levels of BDNF, FGF2, and TrkB/Akt signaling pathway, while inhibiting RIP1-induced RIP1/RIP3/MLKL pathway, thereby antagonizing apoptosis and maintaining neuronal activity. CONCLUSIONS: CE effectively eliminated the toxicity of Aß in cultured neurons and mouse models, which holds promise for drug development.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside Restores BDNF-TrkB and FGF2-Akt Signaling Axis to Attenuate Stress-induced Depression.

Depression is a long term inhibitory mood that heavily disabled human beings. We have previously demonstrated anti-depression effect of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucoside (THSG) in chronic-restraint stress (CRS) induced depressive-like mice by restoring the oxidative pathway and neuroinflammation. In this study, we examine the conditions of neurotrophins in CRS-induced depressive-like mice and whether THSG could be an antidepressant by ameliorating the neurotrophins and their associated signaling axis. CRS produced downregulation of antioxidants, the decline of brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and associated signaling regulators in the hippocampus and prefrontal cortex, corresponding to the behavioral inability and anhedonia. Administration of THSG restored the expression of antioxidants and neurotrophins BDNF, FGF2. Besides, THSG recovered the Akt signaling pathway and antagonistically restored the expression of Bcl-2 and cleaved-caspase-3 to inhibit apoptosis. Consistently, behavioral performances were recovered from CRS-induced motor inability and anhedonia. In summary, THSG is effective to attenuate stress-induced depression by ameliorating the biochemistry of neurotrophins and their related signaling pathways. These results may provide an avenue to take BDNF as a target to explore folk medicine for anti-depression.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside attenuates MPP+/MPTP-induced neurotoxicity in vitro and in vivo by restoring the BDNF-TrkB and FGF2-Akt signaling axis and inhibition of apoptosis.

The major bioactive ingredient THSG of Polygonum multiflorum is well established for its anti-oxidation, anti-aging and anti-inflammation properties. Increasing evidence supports the capacity of THSG to ameliorate the biochemistry of neurotrophins and their downstream signaling axis in mouse models to attenuate neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this study, the neuroprotective effects of THSG were studied in vitro and in vivo. In cultured mesencephalic dopamine neurons and SH-SY5Y cell line, it was found that THSG protected the integrity of the cell body and neurite branching from MPP+-induced toxicity by restoring the expression of FGF2 and BDNF and their downstream signaling pathways to inhibit apoptosis and promote cell survival. The inhibition of Akt signaling by LY294002 or TrkB activity by K252a eliminated the neuroprotective effects of THSG. In the MPTP-induced mouse models of Parkinson's disease, THSG ameliorated the animal behaviors against MPTP-induced neurotoxicity, which was demonstrated by the pole test and the tail suspension test. Biochemical and immunohistochemical analysis verified the THSG-mediated restoration of the FGF2-Akt and BDNF-TrkB signaling axis in the substantia nigra and corpus striatum and the recovery of dopaminergic neurons. These results establish the neuroprotective effects of THSG in vitro and in vivo and unravel the underlying mechanism against toxin-induced neural atrophy, providing a new avenue for the use and pharmacological research of edible medicine for anti-neurodegenerative diseases.