Combination of tea polyphenols and proanthocyanidins prevents menopause-related memory decline in rats via increased hippocampal synaptic plasticity by inhibiting p38 MAPK and TNF-α pathway.

OBJECTIVE: Many studies have examined the beneficial effects of tea polyphenols (TP) and proanthocyanidins (PC) on the memory impairment in different animal models. However, the combined effects of them on synaptic, memory dysfunction and molecular mechanisms have been poorly studied, especially in the menopause-related memory decline in rats. METHODS: In this rat study, TP and PC were used to investigate their protective effects on memory decline caused by inflammation. We characterized the learning and memory abilities, synaptic plasticity, AMPAR, phosphorylation of the p38 protein, TNF-ɑ, structural synaptic plasticity-related indicators in the hippocampus. RESULTS: The results showed that deficits of learning and memory in OVX + D-gal rats, which was accompanied by dendrites and synaptic morphology damage, and increased expression of Aß1-42 and inflammation. The beneficial effects of TP and PC treatment were found to prevent memory loss and significantly improve synaptic structure and functional plasticity. TP+PC combination shows more obvious advantages than intervention alone. TP and PC treatment improved behavioral performance, the hippocampal LTP damage and the shape and number of dendrites, dendritic spines and synapses, reduced the burden of Aß and decreased the inflammation in hippocampus. In addition, TP and PC treatment decreased the expressions of Iba-1, TNF-α, TNFR1, and TRAF2. CONCLUSIONS: These results provided a novel evidence TP combined with PC inhibits p38 MAPK pathway, suppresses the inflammation in hippocampus, and increase the externalization of AMPAR, which may be one of the mechanisms to improve synaptic plasticity and memory in the menopause-related memory decline rats.

Tea polyphenols ameliorates memory decline in aging model rats by inhibiting brain TLR4/NF-κB inflammatory signaling pathway caused by intestinal flora dysbiosis.

AIMS: Tea is a rich source of pharmacologically active molecules that has been suggested to provide a variety of health benefits. However, its mechanism of action in aging-related intestinal flora dysbiosis mediated neuroinflammation is still unclear. This study aimed to explore whether tea polyphenols (TP) can improve memory by regulating intestinal flora mediated neuroinflammation in aging model rats. METHODS: Ovariectomy (OVX) combined with D-galactose injection was used to establish aging rats related to menopause. The rats were divided into Sham control group, Aging model group, TP 75 mg/kg, 150 mg/kg, 300 mg/kg groups and VE group. After 12 weeks of intervention, the shuttle box test and Y maze test were used to check the memory of rats. The composition of intestinal flora was assessed by 16S rRNA sequencing technology. HE staining and ELISA were used to detect intestinal epithelial morphology and permeability, respectively. TLR4/NF-κB inflammation pathway related indicators were investigated by western blot, and the microglia activation in rat hippocampal tissue was checked by immunofluorescence. RESULTS: In the shuttle box test and the Y maze test, compared with the Sham control group, the memory of Aging model rats was significantly declined. It was observed that the intestinal flora of Aging model rats was dysbiosis, the permeability of the intestinal epithelium was increased. Further experimental results showed that the expression of TLR4/NF-κB inflammatory pathway related proteins in the hippocampus were increased, and the excessive activation of microglia was observed. The beneficial effects of TP intervention have been found to prevent memory decline and significantly improve brain inflammation induced by intestinal flora dysbiosis, and TP 300 mg/kg showed a more obvious advantage than TP 75 mg/kg. TP 300 mg/kg can significantly improve the behavior of rats, improve the composition and diversity of the intestinal flora, and the shape and function of the intestinal epithelium. By reversing the increased expression levels of TLR4, IRAK, p-IκBα and nuclear NF-κB p65 proteins in the hippocampus of Aging model rats, the activation of microglia in the CA1, CA3 and Dentate gyrus (DG) sub-regions of the hippocampus can be inhibited. CONCLUSION: TP inhibits the brain TLR4/NF-κB inflammatory signal pathway caused by the dysbiosis of intestinal flora, which may be one of the mechanisms to improve the memory decline in aging model rats.

[Protective effect of 1, 25(OH)_2D_3 on Aß_(1-42)-induced pyrolysis in PC12 cells].

OBJECTIVE: To investigate the protective effect of 1, 25(OH)_2D_3 on Aß_(1-42)-induced pyrolysis in PC12 cells. METHODS: The Alzheimer& apos; s disease model in PC12 cells was established with 20 µmol/L Aß_(1-42). The experiment was divided into control group, model group(20 µmol/L Aß_(1-42)) and 1, 25(OH)_2D_3 groups(1, 10, 100 nmol/L 1, 25(OH)_2D_3+20 µmol/L Aß_(1-42)). Cell activity was detected by CCK-8, cell membrane permeability was detected by AO/EB staining, lactic dehydrogenase(LDH)and interleukin-1ß(IL-1ß)were detected by colorimetry and ELISA, NOD-like receptor family protein 1(NLRP1), cysteinyl aspartate specific proteinase-1(caspase-1)and gasdermin D(GSDMD)protein expression were detected by Western Blot. RESULTS: Compared with the control group, the cell activitywas significantly decreased(P& lt; 0. 01), cell membrane permeability, the level of LDH and IL-1ß, and the expression of NLRP1, caspase-1 and GSDMD were significantly increased(P& lt; 0. 01). Compared with the model group, the cell activity was significantly increased(P& lt; 0. 01), cell membrane damage was decreased in PC12 cells exposed to 1, 25(OH)_2D_3. The level of LDH and IL-1ß were significantly decreased(P& lt; 0. 01) in PC12 cells exposed to 10 and 100 nmol/L 1, 25(OH)_2D_3. The expression of NLRP1 and GSDMD in 1 nmol/L 1, 25(OH)_2D_3 group was decreased(P& lt; 0. 05), and the decrease was more significant in 10 and 100 nmol/L 1, 25(OH)_2D_3 groups(P& lt; 0. 01). The expression of caspase-1 was significantly decreased in 10 and 100 nmol/L 1, 25(OH)_2D_3 groups(P& lt; 0. 05, P& lt; 0. 01). CONCLUSION: 1, 25(OH)_2D_3 exerts a significant protective effect against Aß_(1-42)-induced PC12 cells injury through inhibition of neuronal pyrolysis.

[Effects of resveratrol combined with soy isoflavones on apoptosis induced by oxidative stress in hippocampus of aging model rats].

OBJECTIVE: To investigate the effect of resveratrol(Res) combined with soy isoflavones(SIF) on apoptosisinduced by oxidative stress in hippocampus in aging model rats. METHODS: Sixty female SD rats were randomly divided into the Sham control group, aging model group, Res treatment group, SIF treatment group, Res combined with SIF treatment group and estrogen replacement therapy group(ERT group). Rats with aging were induced by bilateral ovariectomy combined with intraperitoneal injection of D-galactose. TUNEL and transmission electron microscopy were used to observe apoptosis and ultrastructural changes of mitochondrion in hippocampus, respectively. The activities of superoxide dismutase(SOD), catalase(CAT), glutathione peroxidase(GSH-Px) and content of Malonaldehyde(MDA) were detected in the hippocampal homogenate. The protein expressions of cytochrome C oxidase(COX) Ⅰ, Bcl-2 associated X protein(Bax)、B-cell leukemia/lymphoma 2(Bcl-2) and cytochrome C were detected by Western blot. RESULTS: Compared with the Sham control group, the number of TUNEL-positive cells and the apoptotic index(AI) in the model group increased. Marked increase of mitochondrial swelling and vacuolation, decrease of mitochondrial integrity were also observed in the model group. Additionally, the levels of SOD, CAT and GSH-Px were decreased and the level of MDA was increased in the model group in the hippocampus, Bax and cytochrome C protein expression increased, and the COX Ⅰ protein expression and the ratio of Bcl-2/Bax decreased(P<0. 05). In compared with the model group, the number of TUNEL-positive cells and AI significantly decreased, mitochondrial integrity improved in all of the treatment groups, the COX Ⅰ protein expression significantly up-regulated, Bax and cytochrome C protein expression down-regulated, and the protein expression ratio of Bcl-2/Bax increased(P<0. 05 or P<0. 01). Compared with the Res alone and SIF alone treatment group, Res combined SIF treatment decreased the AI and Bax, cytochrome C protein expression, moreover, increased the mitochondrial integrity rate, COX Ⅰ and Bcl-2/Bax protein expression ratio(P<0. 05). There was no statistically significant difference in Bcl-2 protein expression among all the groups(P>0. 05). CONCLUSION: Res and SIF alone and in combination decreased apoptosisinduced by oxidative stress in hippocampus of aging model rats, and beneficial effect in the Res combined SIF treatment group is more significant than that in the alone administration. Improving the antioxidant capacity, increasing the protein expressions of COX Ⅰ andthe ratio of Bcl-2 and Bax, and inhibiting the release of cytochrome C may be the mechanisms by which Res and SIF improve apoptosis in aging rats.

TMC1 is an essential component of a leak channel that modulates tonotopy and excitability of auditory hair cells in mice.

Hearing sensation relies on the mechano-electrical transducer (MET) channel of cochlear hair cells, in which transmembrane channel-like 1 (TMC1) and transmembrane channel-like 2 (TMC2) have been proposed to be the pore-forming subunits in mammals. TMCs were also found to regulate biological processes other than MET in invertebrates, ranging from sensations to motor function. However, whether TMCs have a non-MET role remains elusive in mammals. Here, we report that in mouse hair cells, TMC1, but not TMC2, provides a background leak conductance, with properties distinct from those of the MET channels. By cysteine substitutions in TMC1, we characterized four amino acids that are required for the leak conductance. The leak conductance is graded in a frequency-dependent manner along the length of the cochlea and is indispensable for action potential firing. Taken together, our results show that TMC1 confers a background leak conductance in cochlear hair cells, which may be critical for the acquisition of sound-frequency and -intensity.