Xenin-25 is a 25-amino acid peptide hormone co-secreted from the same enteroendocrine K-cell as the incretin peptide glucose-dependent insulinotropic polypeptide. There is no known specific receptor for xenin-25, but studies suggest that at least some biological actions may be mediated through interaction with the neurotensin receptor. Original investigation into the physiological significance of xenin-25 focussed on effects related to gastrointestinal transit and satiety. However, xenin-25 has been demonstrated in pancreatic islets and recently shown to possess actions in relation to the regulation of insulin and glucagon secretion, as well as promoting beta-cell survival. Accordingly, the beneficial impact of xenin-25, and related analogues, has been assessed in animal models of diabetes-obesity. In addition, studies have demonstrated that metabolically active fragment peptides of xenin-25, particularly xenin-8, possess independent therapeutic promise for diabetes, as well as serving as bioactive components for the generation of multi-acting hybrid peptides with antidiabetic potential. This review focuses on continuing developments with xenin compounds in relation to new therapeutic approaches for diabetes-obesity.

Research has focused mainly on the acquisition phase of spatial tasks, while retention has been relatively ignored. In three experiments, we determine the type of information that is retained in spatial memory using the water maze task. In experiment 1, we demonstrate that by rotating the distal cues 180 degrees post-acquisition Wistar rats search in the opposite area to where the platform should be. This search continues for a maximum of 30 s. We then demonstrate (experiment 2) that by rotating the starting position (180 degrees post-acquisition) animals remain at the starting-point for 10 s. They then commence searching in the platform area. In experiment 3, we demonstrate that rotations of distal cues and starting position post-acquisition impair retention of the platform's location. We suggest that the association between the configuration of distal cues and platform location is retained in memory but the association is fragile and sensitive to disruption.

Among the many reported effects of irradiation in cells is activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), which has been shown to result in apoptotic cell death. The trigger that leads to JNK activation has not been identified, although, in rat hippocampus at least, irradiation-induced apoptosis has been coupled with increased accumulation of reactive oxygen species (ROS). Significantly, irradiation-induced changes in hippocampus are abrogated by treatment of rats with the polyunsaturated fatty acid, eicosapentaenoic acid (EPA). A close coupling between ROS accumulation and concentration of the pro-inflammatory cytokine, interleukin-1␤ (IL-1␤) in hippocampus has been reported, and the evidence suggests that IL-1␤ may be responsible for the enhanced ROS production. Here we set out to assess the possibility that whole body ␥-irradiation increases IL-1␤ concentration in hippocampus and to investigate the consequences of such a change. We present evidence that reveals that the irradiation-induced increase in IL-1␤ concentration in hippocampus is accompanied by increased expression of IL-1 type I receptor and IL-1 accessory protein and increased activation of IL-1 receptor-activated kinase. These changes, which were coupled with increased activation of JNK and evidence of apoptotic cell death, were absent in hippocampus of rats that received EPA treatment. Significantly, EPA treatment enhanced hippocampal IL-10 concentration that was inversely correlated with IL-1␤ concentration. The data are consistent with the idea that EPA exerts anti-inflammatory and neuroprotective effects in the central nervous system.

The hippocampus communicates with the neocortex via the entorhinal cortex and is thought to be critically involved in the consolidation of memories. This paper contains in vivo evidence of a projection from the hippocampal area CA1 to the entorhinal cortex. Current theories of memory formation suggest that the backprojections from the hippocampus to the neocortex should undergo some form of plastic change in order that memories become consolidated. Paired-pulse facilitation (PPF) and long-term potentiation (LTP) are forms of short- and long-term plasticity, respectively. We show that the CA1 to entorhinal cortex projection is capable of sustaining PPF over a wide range of stimulus intervals. In addition we demonstrate that following high frequency stimulation of this pathway the evoked response in the entorhinal cortex remains potentiated for at least 30 min. Finally, we demonstrate that PPF changes following LTP depending on the initial ratio of PPF, suggesting that LTP expression on this pathway may contain a presynaptic component. These findings should provide insight into the hippocampal function in memory formation.

Xenin-25 undergoes rapid enzyme metabolism following secretion. Early studies demonstrated bioactivity of a C-terminal hexapeptide fragment of xenin-25, namely xenin-6, which were enhanced through introduction of a reduced N-terminal peptide bond, to yield Ψ-xenin-6. The present study was undertaken to define the biological actions and potential antidiabetic properties of Ψ-xenin-6. In vitro enzymatic stability, insulin and glucagon secretory activity, as well as effects on beta-cell survival were determined. Studies in mice were used to assess the impact of Ψ-xenin-6 on glucose homeostasis and satiety. Ψ-xenin-6 was resistant to murine plasma degradation. In BRIN-BD11 cells and isolated murine islets, Ψ-xenin-6 significantly stimulated insulin secretion, and prominently enhanced the insulinotropic actions of GIP. Xenin-6 and Ψ-xenin-6 had no impact on glucagon secretion, although xenin-6 partially reversed the glucagonotropic action of GIP. Further in vitro investigations revealed that, similar to GLP-1, Ψ-xenin-6 significantly augmented proliferation of human and rodent clonal betacells, whilst also fully protecting against cytokine-induced beta-cell cytotoxicity, with greater potency than xenin-25 and xenin-6. When administered to mice in combination with glucose, Ψ-xenin-6 significantly reduced glucose levels and enhanced glucose-induced insulin release, with a duration of biological action beyond 8 hours. Ψ-xenin-6 also significantly enhanced the glucose-lowering action of GIP in vivo. In overnight fasted mice, Ψ-xenin-6 exhibited satiety actions at both 25 and 250 nmol/kg. These data demonstrates that Ψ-xenin-6 is a metabolically stable C-terminal fragment analogue of xenin-25, with a metabolic action profile that merits further study as a potential antidiabetic compound.