RESUMEN
OBJECTIVES: Diabetes mellitus is frequently accompanied by depression (diabetes-depression, DD), and DD patients are at higher risk of diabetes-related disability and mortality than diabetes patients without depression. Hippocampal degeneration is a major pathological feature of DD. Here, we investigated the contribution of the Glu-mGluR2/3-ERK signaling pathway to apoptosis of hippocampal neurons in DD model rats. METHODS: The DD model was established by high-fat diet (HFD) feeding and streptozotocin (STZ) injection followed by chronic unpredictable mild stress (CUMS). Other groups were subjected to HFD + STZ only (diabetes alone) or CUMS only (depression alone). Deficits in hippocampus-dependent memory were assessed in the Morris water maze (MWM), motor activity in the open field test (OFT), and depression-like behavior in the forced swim test (FST). Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) was used to estimate the rate of hippocampal neuron apoptosis. Hippocampal glutamate (Glu) content was measured by high performance liquid chromatography. Hippocampal expression levels of mGluR2/3, ERK, and the apoptosis effector caspase-3 were estimated by immunohistochemistry and Western blotting. RESULTS: DD model rats demonstrated more severe depression-like behavior in the FST, greater spatial learning and memory deficits in the MWM, and reduced horizontal and vertical activity in the OFT compared to control, depression alone, and diabetes alone groups. All of these abnormalities were reversed by treatment with the mGluR2/3 antagonist LY341495. The DD group also exhibited greater numbers of TUNEL-positive hippocampal neurons than all other groups, and this increased apoptosis rate was reversed by LY341495. In addition, hippocampal expression levels of caspase-3 and mGluR2/3 were significantly higher, ERK expression was lower, and Glu was elevated in the DD group. The mGluR2//3 antagonist significantly altered all these features of DD. CONCLUSIONS: Comorbid diabetes and depression are associated with enhanced hippocampal neuronal apoptosis and concomitantly greater hippocampal dysfunction. These pathogenic effects are regulated by the Glu-mGluR2/3-ERK signaling pathway.
RESUMEN
Diagnosis with breast cancer is a major life event that elicits increases in depressive symptoms for up to 50% of women. Xiaoyao Kangai Jieyu Fang (XYKAJY) is derived from a canonical TCM formula, Xiaoyao San (XYS), which has a history of nearly 1000 years for treating depression. The aim of this study was to investigate whether XYKAJY alleviates depression-like behavior and breast tumor proliferation in breast cancer mice then explore the mechanisms underlying its action on HPA axis and hippocampal plasticity further. XYKAJY was treated at the high dose of 1.95 g/mL and 0.488 g/mL, after 21 days of administration. Different behaviors, monoamine neurotransmitters, tumor markers, and the index of HPA axis were detected to evaluate depressive-like symptoms of breast cancer mice. Also, the pathological changes of the tumor, hippocampus, and the expressions of GR, NR2A, NR2B, CAMKII, CREB, and BDNF were detected. In this study, XYKAJY formulation significantly improved the autonomic behavior, reduced the incubation period of feeding, and reversed the typical depressive-like symptoms in breast cancer mice. Also, it reduced the content of CORT, ACTH, CRH, and CA125, CA153, CEA in the blood, protected the pathological changes of the hippocampus and tumor, upregulated the expression of GR, CREB, and BDNF in the hippocampus, and significantly decreased the expression of NR2A, NR2B, and CaMKII. These results provide direct evidence that XYKAJY effectively alleviates depression-like behaviors and tumor proliferation in vehicle mice with ameliorates hippocampus synaptic plasticity dysfunctions.