Activation of imidazoline‐I3 receptors ameliorates pancreatic damage

Abstract

Agmatine, an endogenous ligand of imidazoline receptors, is reported to exhibit anti-hyperglycaemic and many other effects. It has been established that the imidazoline I3 receptor is involved in insulin secretion. The current study characterizes the role of the imidazoline I3 receptor in the protection of pancreatic islets. The activity effect of agmatine against on streptozotocin (STZ)-induced (5 mmol/L) rat b cell apoptosis was examined by using ApoTox-Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and western blot. Imidazoline I3 receptors antagonist KU14R and the phospholipase C inhibitor named U73122 were treated in b cells to investigate the potential signalling pathways. The serum glucose and recovery of insulin secretion were measured in STZ-treated rats after continuously injected agmatine. The apoptosis in rat b cells was reduced by agmatine in a dose-dependent manner, cell viability was improved after treatment with agmatine and these effects were suppressed after the blockade of KU14R and U73122. Western blot analysis confirmed that agmatine could decrease caspase-3 expression and increase the p-BAD levels. In STZ-treated rats, injection of agmatine for 4 weeks may significantly lower the serum glucose and recovery of insulin secretion. This improvement of pancreatic islets induced by agmatine was deleted by KU14R in vivo. Agmatine can activate the imidazoline I3 receptor linked with the phospholipase C pathway to induce cell protection against apoptosis induced by a low dose of STZ. This finding provides new insight into the prevention of early stage pancreatic islet damage.

Investigation of morin‐induced insulin secretion in cultured pancreatic cells

“…Therefore, multiple effects of KU14R, in addition to the blockade of I‐3R, should be considered. However, with careful application at the effective dose and a suitable target, KU14R can inhibit I‐3R, as described recently . In MIN6 cells, our results demonstrated that KU14R is effective in inhibiting morin at the same dose for the blockade of efaroxan.…”

“…However, with careful application at the effective dose and a suitable target, KU14R can inhibit I-3R, as described recently. 47,48 In MIN6 cells, our results demonstrated that KU14R is effective in inhibiting morin at the same dose for the blockade of efaroxan. Additionally, KU14R did not enhance insulin secretion directly in MIN6 cells.…”

Imidazoline Receptor System: The Past, the Present, and the Future

“…Once the concept of imidazoline receptors was accepted by a large number of scientists interested in the potential therapeutic effects and uses of drugs targeting these receptors, they were quickly subdivided into three subtypes: I 1 , I 2 and I 3 . This classification results from biochemical, pharmacological, and functional characterizations (Vauquelin et al, 1999; Morgan and Chan, 2001; Dardonville and Rozas, 2004;Li et al, 2015). This work will also describe the most recent prospects for I 2 and I 3 imidazoline receptors and their possible new clinical applications.…”

Agmatine Reduces Lipopolysaccharide-Mediated Oxidant Response via Activating PI3K/Akt Pathway and Up-Regulating Nrf2 and HO-1 Expression in Macrophages

“…Imidazoline receptors play important roles in cell proliferation, neuroprotection, inflammation and psychiatric disorders [ 40 ]. Three subtypes of imidazoline receptors have been identified, and all have been reported to contain a binding site for agmatine [ 41 , 42 ]. A previous report suggested that agmatine exerts its neuroprotective effects through a mechanism that involves Nrf2 induction via α2-adrenergic and 5-HT2A receptors in HT22 cells.…”