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

Abstract

Macrophages are key responders of inflammation and are closely related with oxidative stress. Activated macrophages can enhance oxygen depletion, which causes an overproduction of reactive oxygen species (ROS) and leads to further excessive inflammatory response and tissue damage. Agmatine, an endogenous metabolite of L-arginine, has recently been shown to have neuroprotective effects based on its antioxidant properties. However, the antioxidant effects of agmatine in peripheral tissues and cells, especially macrophages, remain unclear. In this study we explored the role of agmatine in mediating antioxidant effects in RAW 264.7 cells and studied its antioxidant mechanism. Our data demonstrate that agmatine is an activator of Nrf2 signaling that markedly enhances Nrf2 nuclear translocation, increases nuclear Nrf2 protein level, up-regulates the expression of the Nrf2 downstream effector HO-1, and attenuates ROS generation induced by Lipopolysaccharide (LPS). We further demonstrated that the agmatine-induced activation of Nrf2 is likely through the PI3K/Akt pathway. LY294002, a specific PI3K/Akt inhibitor, abolished agmatine-induced HO-1 up-regulation and ROS suppression significantly. Inhibiting HO-1 pathway significantly attenuated the antioxidant effect of agmatine which the products of HO-1 enzymatic activity contributed to. Furthermore, the common membrane receptors of agmatine were evaluated, revealing that α2-adrenoceptor, I1-imidazoline receptor or I2-imidazoline receptor are not required by the antioxidant properties of agmatine. Taken together, our findings revealed that agmatine has antioxidant activity against LPS-induced ROS accumulation in RAW 264.7 cells involving HO-1 expression induced by Nrf2 via PI3K/Akt pathway activation.

Agmatine protects against sodium valproate–induced hepatic injury in mice via modulation of nuclear factor‐κB/inducible nitric oxide synthetase pathway

“…Agmatine may exert antioxidant effect by decreasing hydrogen peroxide level and protecting the oxidation of sulfhydryl group . Recent study has declared that agmatine may activate nuclear factor erythroid 2–related factor 2 resulting in the upregulation of heme oxygenase‐1, thus decreasing the generation of ROS …”

Effect of Agmatine Sulfate on Modulation of Matrix Metalloproteinases via PI3K/Akt-1 in HT1080 Cells

“…Therefore, we screened for natural compounds that inhibit MMPs and cell invasion. In this study, we investigated the effect of agmatine sulfate on metastasis related to the expression MMP-2 in human fibrosarcoma cells (17). In this study, we examined the inhibitory effect of agmatine sulfate on the activity of PMSinduced MMPs using gelatin zymography in HT1080 cells.…”

Therapeutic potential of agmatine in the experimental autoimmune encephalomyelitis

“…It exerts neuromodulation properties, particularly assuring the control and modulation of NO pathway, influencing glutamate N-methyl-D-aspartate (NMDA) receptors and limiting oxidative/ nitrosative stress development. By its antioxidant activities, AGM reveals neuroprotective outcomes 17 . We proposed that treatment with AGM administered during the acute phase of EAE would attenuate disease severity, both clinically and biochemically.…”