Yueju confers antidepressant effects in a rapid and long-lasting manner, similar to ketamine. CREB (cAMP-response element binding protein) signaling is implicated in depression pathology and antidepressant responses. However, the role of CREB and associated brain derived neurotrophic factor (BDNF) signaling in rapid and long-lasting antidepressant effects remains unclear. Here, we demonstrated that ICR and Kunming strain mice conferred antidepressant responses lasting for 1 and 5 days, respectively, following a single dose of Yueju. One day post Yueju in Kunming but not ICR strain mice, expression of total and phosphorylated CREB, as well as the CREB signaling activator, PKA (protein kinase A) was up-regulated in the hippocampus. Although BDNF gene expression increased at 3 hours in both strains, it remained up-regulated at 1 day only in Kunming mice. Ketamine showed similar strain-dependent behavioral effects. However, blockade of PKA/CREB signaling blunted the antidepressant effects and reversed the up-regulation of BDNF gene expression by Yueju, but not ketamine. Conversely, blockade of mammalian target of rapamycin signaling led to opposite effects. Taken altogether, prolonged transcriptional up-regulation of hippocampal BDNF may account for the stain-dependent enduring antidepressant responses to Yueju and ketamine, but it was mediated via PKA/CREB pathway only for Yueju.

Memantine, an aminodamantane, has recently been approved to treat moderate-to-severe Alzheimer's disease in the US after over 20 years on the market in Europe for treatment of Parkinson's disease. The unique properties of Memantine allow for its selective inhibition of abnormally active NMDA receptor channels while preserving normal glutamate activity and healthy neuronal function. Recently, it has been shown that compounds such as nitroglycerin, used for years for ischemic coronary disease, can also regulate the NMDA receptor channel. Novel compounds have been synthesized in an attempt to combine these activities, in an attempt to synergistically improve upon the activities of both nitrates and aminoadamantanes. We have subjected these compounds to several laboratory tests to compare their ability to affect the function of the NMDA receptor and to dilate blood vessels. These tests provide an initial indication of which of the compounds may have enhanced activity relative to memantine. The results also provide guidance for the synthesis of additional compounds that are likely to have the properties that are being sought.

Ethanol extract of Yueju pill, a Traditional Chinese Medicine herbal formula widely used to treat mood disorders, demonstrates rapid antidepressant effects similar to ketamine, likely via instant enhancement of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Here we investigated ethanol extracts of the constituent herbs of Yueju responsible for rapid antidepressant effects. Screening with tail suspension test in Kunming mice at 24 hours after a single administration of five individual constituent herbs of Yueju, we found that only Gardenia jasminoides Ellis (GJ) showed a significant effect. The antidepressant response started at 2 hours after GJ administration. Similar to Yueju and ketamine, a single administration of GJ significantly reduced the number of escape failures in the learned helplessness test. Furthermore, GJ decreased latency of food consumption in the novelty suppressed-feeding test. Additionally, starting from 2 hours and continuing for over 20 hours after GJ administration, BDNF expression in the hippocampus was upregulated, temporally linked with the antidepressant response. These findings suggest that GJ has rapid antidepressant effects, which are associated with the elevated expression of BDNF in the hippocampus. In Yueju formula, Yue represents GJ, as thus our study demonstrates the primary role of GJ in rapid antidepressant efficacy of Yueju.

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ObjectiveThis study aimed to evaluate Serum 25-hydroxyvitamin D (25[OH]D) levels in diabetic men with and without hypogonadism and figured out the potential factors influencing the connection between vitamin D and testosterone.MethodsA total of 367 men with type 2 diabetes mellitus (T2DM) were investigated, including 254 men with normal gonadal function (Group 1) and 113 men with hypogonadism (Group 2). Men with hypogonadism were classified as either hypogonadotropic hypogonadism (Group 2a) or hypergonadotropic hypogonadism (Group 2b). Serum 25(OH)D levels were detected by liquid chromatography-tandem mass spectrometry in all cases. Morning total testosterone (TT), estradiol (E), dehydroepiandrosterone (DHEA), prolactin (PRL), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid function, parathyroid and adrenal hormones, fasting blood glucose (FBG), fasting insulin (Fins) and hemoglobin A1c (HbA1c) were also assessed.ResultsThe prevalence of hypovitaminosis D in men with T2DM was up to 96.46%. Serum 25(OH)D levels were significantly lower in men with hypogonadism than those with eugonadism (16.65 ± 6.44 ng/mL vs. 18.17 ± 6.17 ng/mL, P=0.033). The lowest 25(OH)D level was observed in Group 2a (16.22 ± 6.52 ng/mL). After adjustment for the selected factors, serum 25(OH)D concentrations were shown to be positively correlated with TT concentrations (r=0.137, P=0.032). The relationship between 25(OH)D and testosterone was altered by age, duration of T2DM, body mass index, and HbA1c. Serum 25(OH)D level was positively associated with serum TT level in men with age <60 years (r=0.180, P=0.003), or with duration≥5 years (r=0.186, P=0.013), or with body mass index (BMI)≥28kg/m2 (r=0.431, P=0.000), or with HbA1c≥9% (r=0.145, P=0.031).ConclusionsThese findings indicate that type 2 diabetes patients with hypogonadism have lower 25(OH)D levels than those without hypogonadism. There seems to be a positive association between the serum 25(OH)D and TT levels, which affected by age, duration, BMI, and HbA1c