[Tea polyphenols improves depression-like behavior in aged type 2diabetes rats by regulating microglia polarization].

OBJECTIVE: To investigate the effect of tea polyphenols(TP) on improving depression-like behavior in aged type 2 diabetes(T2DM) model rats. METHODS: A total of 40 8-week-old SD male rats were randomly divided into the control group(n=10) and the modeling group(n=30) according to the body weight. The rats in the modeling group were fed with high-glucose and high-fat diet and treated with 50 mg/kg D-galactose by intraperitoneal injection daily until the end of the experiment, while the rats in the control group were fed with the standard diet and treated with an equal volume of saline by intraperitoneal injection. After 4 weeks, the rats in the modeling group were injected with 25 mg/kg STZ, meanwhile the rats in the control group were injected with an equal volume of citric acid buffer. The level of fasting blood glucose(FBG) was measured on the 14~(th) day. When FBG≥16.7 mmol/L, the rats were identified as successful model of the T2DM rats. Then, the model rats were randomly divided into the model group, 150, 300 mg/kg TP groups(n=10, respectively), and the rats were given intragastric intervention for 8 weeks. The levels of the FBG were detected, and the depression-like behavior of rats was assessed by the open field test(OFT) and forced swimming test(FST). The density of microglia in hippocampus CA1 region was assessed by immunofluorescence staining, and protein expressions of P53, Iba1, iNOS, Arg-1 and BDNF were determined by western blot. RESULTS: Compared with the control group, the levels of FBG in the rats of the model group were obviously increased(P<0.01). In the OFT, the frequencies of rearing and grooming in the rats of model group markedly was decreased, while in the FST, the immobility time extensively was increased(P<0.01). The density of microglia in hippocampus CA1 region was increased(P<0.01). The expressions of P53, Iba1 and iNOS were increased, and the expressions of Arg-1 and BDNF were decreased(P<0.01). Additionally, compared with the model group, in the OFT, the frequencies of rearing and grooming were increased in the rats in 150 and 300 mg/kg TP group(P<0.01). The density of microglia in hippocampus CA1 region was decreased(P<0.01). The expressions of P53, Iba1 and iNOS were down-regulated, and the expression of BDNF was up-regulated(P<0.01). Additionally, compared with the model group, the levels of FBG was decreased in the rats in the 300 mg/kg TP group(P<0.01). The immobility time was decreased in the FST(P<0.01). The expression of Arg-1 was down-regulated(P<0.01). CONCLUSION: TP can improve depression-like behavior in aged T2DM model rats, and its mechanism may be related to regulate microglia M1/M2 polarization and up-regulate expression of BDNF in hippocampus.

Targeting ERS-mitophagy in hippocampal neurons to explore the improvement of memory by tea polyphenols in aged type 2 diabetic rats.

Increasing evidence demonstrated that mitophagy and endoplasmic reticulum stress (ERS) was closely associated with memory decline in elderly type 2 diabetes mellitus (T2DM). Tea polyphenols (TP), an excellent natural antioxidant, has been reported to have neuroprotective properties in aging and diabetes, but the underlying mechanisms are still not fully understood. This study targets ERS-mitophagy in hippocampal neurons to investigate the improvement effect of memory in aged T2DM rats by TP. Rats were randomly divided into the control group, the aged group, the aged T2DM model group, the TP 75, 150, 300 mg/kg groups. TP 300 mg/kg ameliorated mitophagy by decreasing the levels of p-mTOR (S2448), P62 and HSP60 and increasing the levels of PINK1 and Parkin, the ratio of LC3Ⅱ/LC3Ⅰ, co-localization of LC3 and HSP60 and the number of autophagosomes and autolysosomes. TP 300 mg/kg attenuated ERS by downregulating the levels of p-PERK, p-eIF2α, ATF4, GRP78 and restoring the ER structure. To further verify epigallocatechin gallate (EGCG), which is the main active component of TP, enhanced mitophagy by inhibiting ERS, PC12 cells were pretreated with ERS activator tunicamycin (TM) or ERS inhibitor 4-phenylbutyric acid (4-PBA). The results showed that the improvement of mitophagy by EGCG was inhibited by TM and promoted by 4-PBA. Collectively, ERS-mitophagy in hippocampal neurons plays a key role in the improvement of memory by TP in aged T2DM rats. This study will provide a new perspective and strategy for the prevention of memory decline in elderly with T2DM.