No abstract

BackgroundAnorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS. Next, we studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6.ResultsIn vitro, we showed that hypothalamic neurons responded to inflammatory mediators by releasing cytokines. This inflammatory response was associated with an increased serotonin release. Mice injected with TNFα and IL-6 showed decreased food intake, associated with altered expression of inflammation-related genes in the hypothalamus. In addition, hypothalamic serotonin turnover showed to be elevated in treated mice.ConclusionsOverall, our results underline that peripheral inflammation reaches the hypothalamus where it affects hypothalamic serotoninergic metabolism. These hypothalamic changes in serotonin pathways are associated with decreased food intake, providing evidence for a role of serotonin in inflammation-induced anorexia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0260-0) contains supplementary material, which is available to authorized users.

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Apoptosis or programmed cell death is an inherent part of the development and homeostasis of multicellular organisms. Dysregulation of apoptosis is implicated in the pathogenesis of diseases such as cancer, neurodegenerative diseases and autoimmune disorders. Tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is able to induce apoptosis by binding death receptor (DR)4 (TRAIL‐R1) and DR5 (TRAIL‐R2), which makes TRAIL an interesting and promising therapeutic target. To identify peptides that specifically interact with DR5, a disulfide‐constrained phage display peptide library was screened for binders towards this receptor. Phage‐displayed peptides were identified that bind specifically to DR5 and not to DR4, nor any of the decoy receptors. We show that the synthesized peptide, YCKVILTHRCY, in both monomeric and dimeric forms, binds specifically to DR5 in such a way that TRAIL binding to DR5 is inhibited. Surface plasmon resonance studies showed higher affinity towards DR5 for the dimeric form then the monomeric form of the peptide, with apparent Kd values of 40 nm versus 272 nm, respectively. Binding studied on cell lines by flow cytometry analyses showed concentration‐dependent binding. Upon co‐incubation with increasing concentrations of TRAIL, the peptide binding was reduced. Moreover, both the monomeric and dimeric forms of the peptide reduced TRAIL‐induced cell death in Colo205 colon carcinoma cells. The peptide, YCKVILTHRCY, or its derivates, may be a useful investigative tool for dissecting signalling via DR5 relative to DR4 or could act as a lead peptide for the development of therapeutic agents in diseases with dysregulated TRAIL‐signalling.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by poor attention, impulse control and hyperactivity. A significant proportion of ADHD patients are also co-morbid for other psychiatric problems including mood disorders and these patients may be managed with a combination of psychostimulants and anti-depressants. While it is generally accepted that enhanced catecholamine signalling via the action of psychostimulants is likely responsible for the cognitive improvement in ADHD, other neurotransmitters including acetylcholine and histamine may be involved. In the present study, we have examined the effect of lisdexamfetamine dimesylate (LDX), an amphetamine pro-drug that is approved for the treatment of ADHD on acetylcholine and histamine efflux in pre-frontal cortex and hippocampus alone and in combination with the anti-depressant s-citalopram. LDX increased cortical acetylcholine efflux, an effect that was not significantly altered by co-administration of s-citalopram. Cortical and hippocampal histamine were markedly increased by LDX, an effect that was attenuated in the hippocampus but not in pre-frontal cortex when co-administered with s-citalopram. Taken together, these results suggest that efflux of acetylcholine and histamine may be involved in the therapeutic effects of LDX and are differentially influenced by the co-administration of s-citalopram. Attention deficit hyperactivity disorder (ADHD) is characterized by poor attention, impulse control and hyperactivity. Some ADHD patients are also co-morbid for mood disorders and may be managed with psychostimulants (e.g. lisdexamfetamine, LDX) and anti-depressants (e.g. s-citalopram). LDX increased the efflux of acetylcholine and histamine, neurotransmitters involved in cognitive function, which were differentially influenced when co-administered with s-citalopram. Acetylcholine and histamine may be involved in the therapeutic effects of LDX and are differentially affected by the co-administration of s-citalopram.