Anti-mTOR monoclonal antibody, clone SN385

AZD6765 (lanicemine) is a non-competitive NMDA receptor antagonist that induces a fast-acting antidepressant effect without presenting psychotomimetic effects. However, the mechanisms underlying its effects remain to be established. In this context, we demonstrated that a single administration of AZD6765 (1 mg/kg, i.p.) was able to induce an antidepressant-like effect in mice submitted to tail suspension test (TST), an effect reversed by LY294002 (a reversible PI3K inhibitor, 10 nmol/site, i.c.v.), wortmannin (an irreversible PI3K inhibitor, 0.1 mu g/site, i.c.v.) and rapamycin (a selective mTOR inhibitor, 0.2 nmol/site, i.c.v.). In addition, the administration of sub-effective doses of AZD6765 (0.1 mg/kg, i.p.) in combination with lithium chloride (non-selective GSK-3 beta inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3 beta inhibitor, (0.01 mu g/site, i.c.v.) caused a synergistic antidepressant-like effect. These results suggest the involvement of PI3K/Akt/mTOR/GSK3 beta signaling in the AZD6765 antidepressant-like effect. In addition, western blotting analysis showed an increased immunocontent of synapsin in the prefrontal cortex and a tendency to an increased immunocontent of this protein in the hippocampus 30 min after AZD6765 administration, but no significant effect of AZD6765 was observed in P70S6K (Thr(389)) phosphorylation and GluA1 immunocontent. A single dose of AZD6765 (3 mg/kg, i.p.), similarly to ketamine (1 mg/kg, i.p.), decreased the latency to feed in the novelty suppressed feeding (NSF) test, a behavioral paradigm that evaluates depression/anxiety-related behavior. This effect was reversed by rapamycin administration, suggesting the activation of mTOR signaling in the effect of AZD in the NSF test. In addition, a single administration of AZD6765 (1 mg/kg, i.p.) or ketamine (1 mg/kg, i.p.) reversed the depressive-like behavior induced by chronic unpredictable stress (CUS). Altogether, the results provide evidence for the fast-acting antidepressant profile of AZD6765, by a mechanism likely dependent on PI3K/Akt/mTOR/GSK3 beta.

Aims: Previous studies have shown the effect of niacin on dairy cow production, but no study on the role of niacin in milk fat synthesis has been performed. Therefore, the purpose of this study was to examine the effect of niacin on milk fat synthesis and its specific mechanism in BMECs. Main methods: In this study, 0.5 mM niacin, a GPR109A-inhibiting plasmid, and an AMPK inhibitor were added to BMECs. Milk fat was measured by a triglyceride kit and BODIPY staining. The protein expression of GPR109A, FASN, SREBP1, AMPK, ACC, mTOR and S6K was measured by Western blotting. The gene expression of GPR109A, FASN, and SREBP1 was analysed by RT-PCR. Key findings: Our results showed that 0.5 mM niacin could significantly reduce milk fat synthesis in BMECs and activate the AMPK/ACC signalling pathway by stimulating GPR109A, reducing the protein expression of pmTOR and p-S6K, and reducing the expression of SREBP1 and FASN in BMECs. Significance: The present study clarified the effect of niacin on milk fat synthesis. The results show that niacin inhibits the synthesis of milk fat in BMECs through the downstream signalling pathway mediated by GPR109A. The function of niacin has been expanded, and knowledge of the new mechanism and signalling pathway will help improve the biosynthesis of milk fat.