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

Abstract

Eugenosedin-A has been demonstrated to possess alpha/beta-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-1beta (IL-beta), IL-6, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) 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 alpha(2)-adrenoceptor antagonist, reduced IL-1beta and TNF-alpha, but it could not inhibit hyperglycaemia. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, and ascorbic acid, an antioxidant, decreased IL-1beta, TNF-alpha contents and hyperglycaemia. Eugenosedin-A and the other agents inhibited Fe(2+)-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 alpha/beta-adrenergic and serotonergic receptors.

Role of Mitochondrial Oxidative Stress in Sepsis

“…Plasma AA in patients with multiorgan failure was significantly lower [34], whereas low concentrations were inversely correlated with increased lipid peroxides [69] a marker of increased oxidative stress. Results from animal models demonstrated that AA ameliorates edema and hypotension and improves arteriolar responsiveness and capillary blood flow [70][71][72][73]. Experiments in healthy volunteers after induction of systemic inflammation by low doses of E. coli endotoxemia revealed that the hyporeactivity can be corrected by high doses of vitamin C, suggesting that oxidative stress may represent an important target for inflammation-induced impaired vascular function [74].…”

Peritoneal Inflammation in Pigs is Associated with Early Mitochondrial Dysfunction in Liver and Kidney

“…Among others, an excessive generation of reactive oxygen species (ROS) during the early inflammatory state associated with oxidative stress activation has been considered as a cause of mitochondrial dysfunction. The pathological impact of oxidative stress in sepsis was confirmed by effective antioxidant therapy [17][18][19][20][21].…”

Pathophysiological changes of gram-negative bacterial infection can be reproduced by a synthetic peptide mimicking loop L7 sequence of Haemophilus influenzae porin

“…Recent data reveal that cardiovascular activity plays a fundamental role in the early responses to inflammation following intravenous injection of subseptic doses of LPS [32]. Our findings demonstrate that loop L7, like the entire porin P2, significantly increased HR and induce a hypotensive effect after 3 h that is still significant after 8 h, indicating a possible cardiovascular dysfunction.…”