Effects of liraglutide on depressive behavior in a mouse depression model and cognition in the probe trial of Morris water maze test.

BACKGROUND: We investigated the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, on a depression-like phenotype in mice exposed to chronic unpredictable stress (CUS). Learning and memory were also assessed using the Morris water maze (MWM) test. METHODS: Liraglutide (0.3 mg/kg/day for 21 days) was administered to mice with or without exposure to CUS. After 21 days of CUS, the forced swim test (FST) was performed to assess its antidepressant effect. To evaluate cognitive function, liraglutide was administered to mice under stress-free conditions for 21 days, and then the MWM test was performed on 6 consecutive days. RESULTS: Chronic liraglutide treatment reduced FST immobility in mice with and without CUS. In the probe trial of the Morris water maze test, the search error rate was reduced and the time spent and path length in the target quadrant and the number of platform crossings were increased. LIMITATION: Additional animal model experiments and molecular level studies are needed to support the results obtained in this study. CONCLUSIONS: Liraglutide appears to exert antidepressant effects and could improve cognitive function. Based on these results, GLP-1 agonists could have potential as novel antidepressants.

Effects of Chronic LY341495 on Hippocampal mTORC1 Signaling in Mice with Chronic Unpredictable Stress-Induced Depression.

In several rodent models, acute administration of the metabotropic glutamate 2/3 (mGlu2/3) receptor antagonist LY341495 induced antidepressant-like effects via a mechanism of action similar to that of ketamine. However, the effects of chronic mGlu2/3 antagonism have not yet been explored. Therefore, we investigated the effects of chronic LY341495 treatment on the mechanistic target of rapamycin complex 1 (mTORC1) signaling and the levels of synaptic proteins in mice subjected to chronic unpredictable stress (CUS). LY341495 (1 mg/kg) was administered daily for 4 weeks to mice with and without CUS exposure. After the final treatment, the forced swimming test (FST) was used to assess antidepressant-like effects. The hippocampal levels of mTORC1-related proteins were derived by Western blotting. Chronic LY341495 treatment reversed the CUS-induced behavioral effects of FST. CUS significantly reduced the phosphorylation of mTORC1 and downstream effectors [eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP-1) and small ribosomal protein 6 (S6)], as well as the expression of synaptic proteins postsynaptic density-95 (PSD-95) and AMPA receptor subunit GluR1 (GluA1) in the hippocampus. However, chronic LY341495 treatment rescued these deficits. Our results suggest that the activation of hippocampal mTORC1 signaling is related to the antidepressant effect of chronic LY341495 treatment in an animal model of CUS-induced depression.

Alpha-fetoprotein and human telomerase reverse transcriptase mRNA levels in peripheral blood of patients with hepatocellular carcinoma.

PURPOSE: Tumor-associated gene expression in peripheral blood reflects the presence of circulating hepatocellular carcinoma (HCC) cells and might be associated with aggressive features of HCC. We assessed the prognostic significance of alpha-fetoprotein (AFP) and human telomerase reverse transcriptase protein (hTERT) mRNA expression in the peripheral blood of HCC patients. METHODS: About 343 HCC patients, treated at the National Cancer Center, Korea, were included in this study. We measured AFP and hTERT mRNA levels in peripheral blood using quantitative real-time reverse transcription polymerase chain reaction. The association between the expression of each gene and survival was analyzed. RESULTS: AFP and hTERT mRNA were detected in 204 (59.5%) and 48 (14.0%) patients with HCC, respectively. The mean AFP copy number was 203 copies/microL (range 0-19992 copies/microL) and that of hTERT was 26 copies/microL (0-1711 copies/microL). AFP mRNA expression was correlated with the number of tumors (P = 0.05), but there were no significant association between hTERT expression and clinical features. There was also no relationship between overall survival and AFP (P = 0.08) or hTERT (P = 0.67) mRNA expression. CONCLUSIONS: This is the first report to evaluate the association between peripheral blood hTERT mRNA expression, and survival of HCC patients. The results indicate that AFP and hTERT mRNA expression in peripheral blood may not be useful HCC prognostic markers.

Association between vascular endothelial growth factor gene polymorphisms and survival in hepatocellular carcinoma patients.

UNLABELLED: Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and progression of tumor, including hepatocellular carcinoma (HCC), and elevated VEGF levels in serum and tissues have been known to be related with poor prognosis in patients with HCC. However, the effect of such polymorphisms of the VEGF gene on HCC prognosis has not been elucidated. In the present study, we investigated the association between VEGF gene polymorphisms and HCC patient prognosis. The study involved 416 HCC patients treated at the National Cancer Center Korea from November 2000 to December 2005. The median patient age was 57 years, and 328 patients (78.8%) were men. A total of 19 polymorphisms were analyzed, and the hazard ratios (HRs) for genotypes and haplotypes were determined in terms of risk for overall survival using Cox proportional hazard regression analysis. Of the 19 alleles, 7 showed no heterozygous allele. PHASE analysis identified a total of 36 haplotypes. The -2578 to -1498 region of the VEGF gene showed a strong linkage disequilibrium (correlation coefficient, r(2) = 0.91; Lewontin's D', D' = 0.982). The adjusted HRs were 0.67 [95% confidence interval (CI), 0.46 to 0.99] for -634CC genotype carriers and 0.57 (95% CI, 0.36 to 0.92) for homozygous haplotype 1 (Ht1: CCGAGCCC at -2578/-1203/-1190/-1179/-1154/-634/-7/+936) carriers compared with noncarriers. CONCLUSION: These findings suggest that VEGF polymorphisms may be significant prognostic indicators for HCC patients.