The role of mitochondrial KATP channel in anti-inflammatory effects of uridine in endotoxemic mice.

In this study, we examined the effects of uridine on plasma cytokine levels, heat shock protein (HSP) 72 expression, and nuclear factor (NF)-κB signaling in spleen lymphocytes after exposure of male BALB/c mice to Escherichia coli lipopolysaccharide (LPS). Mice were treated with uridine (30 mg/kg body weight, intraperitoneal injection [i.p.]) or saline solution of LPS (2.5 mg/kg, i. p.). Endotoxin increased plasma levels of tumor necrosis factor-α, interferon-γ, interleukin (IL)-1, IL-2, and IL-6 by 2.1-, 1.9-, 1.7-, 1.6-, and 2.3-fold, respectively. Prior treatment with uridine prevented LPS-induced increases in all studied cytokines. In splenic lymphocytes, LPS treatment increased the expression of HSP 72 by 2.4-fold, whereas preliminary treatment with uridine completely prevented this effect. LPS also activated NF-κB signaling in splenic lymphocytes, and uridine decreased NF-κB pathway activity. Inhibitory analysis showed that the mechanism of uridine action was associated with the formation of the UDP-metabolic activator of the mitochondrial ATP-dependent potassium channel (mitoK) and the UTP-activator of glycogen synthesis in the tissues. A specific inhibitor of mitoK, 5-hydroxydecanoate (5 mg/kg), and an inhibitor of glycogen synthesis, galactosamine (110 mg/kg), prevented the effects of uridine. Thus, uridine itself or uridine phosphates, which increased after uridine treatment, appeared to inhibit pro-inflammatory responses induced by LPS application. Overall, these findings demonstrated that the mechanisms mediating the effects of uridine were regulated by activation of glycogen synthesis and opening of the mitoK, which in turn increased the energy potential of the cell and reduced oxidative stress.