AdipoRon, an Orally Active, Synthetic Agonist of AdipoR1 and AdipoR2 Receptors Has Gastroprotective Effect in Experimentally Induced Gastric Ulcers in Mice

Abstract

Introduction: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. Methods: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1β, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. Results: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1β expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. Conclusions: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers.

Distribution of Adiponectin Receptors in the Brain of Adult Mouse: Effect of a Single Dose of the Adiponectin Receptor Agonist, AdipoRON, on Ischemic Stroke

“…In our study, we report that a single injection of AdipoRON (5 mg.kg −1 , a dose known to activate both AdipoR, and to exhibit gastroprotective effects [43]) did not limit the infarct size and apoptosis 24 h after stroke. In addition, Nrf2 gene expression known to be upregulated after oxidative stress conditions, was significantly higher in the ischemic versus contralateral hemisphere.…”

“…Furthermore, in other CNS pathologies, AdipoRON (50 mg.kg −1 ) prevents the behavioral defects, the impaired neurogenesis and neuronal death observed in APP/PS1 Tg Alzheimer mice [56]. The anti-inflammatory and anti-oxidative properties of AdipoRON were also observed in other models (diabetes and gastric ulcers) demonstrating the efficiency of this compound [43,57]. AdipoRON could also have an interesting impact on brain plasticity through the modulation of neurogenesis and trophic factors such as brain-derived neurotrophic factor (BDNF) [58].…”

“…In the light of these data, AdipoRON was used at 5 mg.kg −1 in our study, a dose comparable to the effective dose of globular adiponectin in ischemia regarding the relative K D value of these ligands for adiponectin receptors. This dose was also the starting dose for beneficial gastroprotective effects in a recent study [43].…”

Adiponectin Enhances Fatty Acid Signaling in Human Taste Cells by Increasing Surface Expression of CD36

“…AdipoRon, an orally active adiponectin receptor agonist, binds with high affinity to the adiponectin receptors AdipoR1 and AdipoR2, which acts via 5’ adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor alpha (PPARα) pathways, respectively [ 10 ]. Importantly, AdipoRon acts in a manner consistent with the activity of adiponectin in a number of physiological systems [ 11 , 12 , 13 , 14 , 15 , 16 ]. Recently, Crosson and colleagues found that adiponectin receptors are highly expressed in mice taste buds [ 17 ].…”

The Antiviral Potential of AdipoRon, an Adiponectin Receptor Agonist, Reveals the Ability of Zika Virus to Deregulate Adiponectin Receptor Expression

“…Based on the deleterious impact of ZIKV on neural progenitor cell proliferation and differentiation, we hypothesized that targeting adiponectin signaling could be an interesting therapeutic avenue for limiting ZIKV-induced damages in fetuses. Therefore, AdipoRon, which might provide a beneficial neuroprotective effect during ZIKV infection, emerged as a relevant, easy-to-use candidate, with already tried-and-tested therapeutic delivery options and efficacy [ 39 , 40 , 41 , 42 ]. To conduct an in vitro study of the effect of AdipoRon treatment on ZIKV infection, we used the A549 epithelial cells.…”