Antioxidant eugenosedin-A protects against lipopolysaccharide-induced hypotension, hyperglycaemia and cytokine immunoreactivity in rats and mice

Abstract

Abstract Eugenosedin-A has been demonstrated to possess α/β-adrenoceptor and serotonergic receptor blocking activities. We have investigated by what mechanisms eugenosedin-A prevents lipopolysaccharide (LPS)-induced hypotension, vascular hyporeactivity, hyperglycaemia, oxidative injury or inflammatory cytokines formation in rats. Intravenous administration of eugenosedin-A, trazodone, yohimbine (1 mg kg−1), aminoguanidine or ascorbic acid (15 mg kg−1) normalized LPS (10 mg kg−1)-induced hypotension. Pretreatment with eugenosedin-A or the other agents 30 min before LPS injection reduced aortic hyporeactivity. LPS-induced increases in plasma interleukin-1β (IL-β), IL-6, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) and blood glucose levels were significantly inhibited by eugenosedin-A (1 mg kg−1, i.v.). The same dose of trazodone, a chloropiperazinylbenzene-type antidepressant, and yohimbine, an α2-adrenoceptor antagonist, reduced IL-1β and TNF-α, but it could not inhibit hyperglycaemia. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, and ascorbic acid, an antioxidant, decreased IL-1β, TNF-α contents and hyperglycaemia. Eugenosedin-A and the other agents inhibited Fe2+-ascorbic acid-induced peroxidation in rat cortex, indicating that those agents had antioxidant effects, with the exception of aminoguanidine. In free radical scavenged experiments, eugenosedin-A and ascorbic acid eliminated peroxyl radicals. All test agents inhibited the LPS-induced increase of malondialdehyde (MDA) content in rat brain homogenates. When mice were administered an intraperitoneal injection of LPS alone, mortality occurred from 4 to 16 h, after which time all were dead. However, eugenosedin-A significantly prolonged the survival time after LPS injection, suggesting that eugenosedin-A protected against LPS-induced cardiovascular dysfunction, hyperglycaemia, tissue injury and inflammatory cytokine production. This was attributable mainly to the antioxidant and peroxyl radical scavenged effects of eugenosedin-A, and which may be, at least in part, due to its blockade on α/β-adrenergic and serotonergic receptors.