M871

Galanin, a peptide expressed in mammalian brain regions, has been implicated in anxiety and depression. Galanin signalling occurs through three G protein-linked receptors (GAL1, GAL2 and GAL3). Galanin regulates the release of neurotransmitters in some brain regions related to anxiety, including the hippocampus. GAL2 is the most abundant galanin receptor in the dorsal hippocampus. In this study, we evaluated whether galanin administered in the dorsal hippocampus affected anxiety-like behaviours of rats. We also investigated if GAL2 receptors are involved in the anxiogenic-like effect of galanin using a GAL2 antagonist, M871. To achieve these objectives, male adult Wistar rats received intra-dorsal hippocampal delivery of galanin (0.3 and 1.0 nmol/0.5 µl) or vehicle in experiment 1 and GAL2 antagonist M871 (1.0 and 3.0 nmol/0.5 µl) or vehicle in experiment 2. Twenty min after administration of drugs, the animals were tested in the elevated plus-maze (EPM). Galanin (1.0 nmol) induced anxiogenic-like behaviours, while the GAL2 receptor antagonist M871 (3.0 nmol) induced anxiolytic-like behaviours in rats exposed to the EPM, indicating a tonic effect of galanin. In experiment 3, we evaluated whether previous infusion of the GAL2 antagonist M871 (1 or 2 nmol) in the dorsal hippocampus would block the anxiogenic-like effect of galanin in rats tested in the EPM. We showed that M871 (2.0 nmol) counteracted the anxiogenic-like effect of galanin infused in the dorsal hippocampus of rats. Altogether, our results provide evidence that galanin promotes pharmacological and tonic anxiogenic-like effects in the dorsal hippocampus, possibly mediated by GAL2 receptors.

Background: Type 2 diabetes mellitus is a complex metabolic disorder associated with obesity, glucose intolerance and insulin resistance. Activation of GALR2 has been proposed as a therapeutic target for the treatment of insulin resistance. The previous studies showed that baicalin could mitigate insulin resistance, but the detailed mechanism of baicalin on insulin resistance has not been fully explored yet. Purpose: In the present study, we evaluated whether baicalin mitigated insulin resistance via activation of GALR2 signaling pathway. Study design/methods: Baicalin (25 mg/kg/d and 50 mg/kg/d) and/or GALR2 antagonist M871 (10 mg/kg/d) were injected individually or in combinations into obese mice once a day for three weeks, and normal and GALR2 knockdown myotubes were treated with baicalin (100 μM and 400 μM) or metformin (4 mM) in the absence or presence of M871 (800 nM) for 12 h, respectively. The molecular mechanism was explored in skeletal muscle and L6 myotubes. Results: The present findings showed that baicalin mitigated hyperglycemia and insulin resistance and elevated the levels of PGC-1α, GLUT4, p-p38MAPK, p-AKT and p-AS160 in skeletal muscle of obese mice. Strikingly, the baicalin-induced beneficial effects were abolished by GALR2 antagonist M871 in obese mice. In vitro, baicalin dramatically augmented glucose consumption and the activity of PGC1α-GLUT4 axis in myotubes through activation of p38MAPK and AKT pathways. Moreover, baicalin-induced elevations in glucose consumption related genes were abolished by GALR2 antagonist M871 or silencing of GALR2 in myotubes. Conclusions: The present study for the first time demonstrated that baicalin protected against insulin resistance and metabolic dysfunction mainly through activation of GALR2-GLUT4 signal pathway. Our findings identified that activation of GALR2-GLUT4 signal pathway by baicalin could be a new therapeutic approach to treat insulin resistance and T2DM in clinic.

In the title complex, [Ag(C(18)H(15)P)(3)(ClO(4))], the silver coord-ination environment is dominated by the distorted P(3)AgO tetra-hedron in which Ag-O = 2.608 (12) Å and the Ag-P bond lengths are 2.5663 (17), 2.5076(16) and 2.5450 (17) Å. The perchlorate O-atoms are disordered over two positions in a 0.584 (14):0.416 (14) ratio.