Propolis derivatives inhibit the systemic inflammatory response and protect hepatic and neuronal cells in acute septic shock

BACKGROUND: Severe pathogenic infection triggers excessive release of cytokines as part of the massive inflammatory response associated with septic shock. OBJECTIVES: To investigate the protective effect of caffeic acid phenethye ester (CAPE) against lipopolysaccharide (LPS) induced endotoxemia, hepatic and neuronal damage and the associated systemic inflammatory response (SIR). METHODS: Fifty male Wister rats were divided into: control, LPS, and CAPE+LPS groups. Plasma concentrations of various cytokines, including TNF-α, IL-1α, IL-1β, IL-6, IL-4, IL-10, and sICAM-1 were evaluated. In addition, the histopathological changes in the hepatic and neural cells were assessed. RESULTS: The LPS group showed high inflammatory cytokines and sICAM-1 levels reflecting the presence of SIR. Hepatocyte necrosis, apoptosis, extensive hemorrhage and inflammatory cellular infiltration together with brain astrocytes swelling, early neuron injury and presence of inflammatory foci confirmed the toxic tissue damage. Use of CAPE decreased the inflammatory cytokines and increased the anti-inflammatory cytokines levels. This biochemical evidence of decreased SIR was confirmed histologically by decreased cellular infiltration in the liver and brain tissue which coincides with preserved structure and protection of the liver and brain cells from the toxic effects of LPS. CONCLUSION: The ability of CAPE to alleviate the SIR, hepatic and neuronal cell damage induced by LPS and galactosamine could be attributed to its ability to reverse the imbalance of the pro- and anti-inflammatory cytokines which may lead to the inhibition of adhesion molecules' expression. CAPE is a promising agent that could help in the prophylaxis and treatment of septic shock.

Effect of administration of galactosamine hydrochloride on rat liver mitochondria.

The effect of galactosamine on liver mitochondrial functions was studied in vivo in rats at 12hr, 24hr and 36hr after the administration of the drug. State 3 respiration decreased significantly with both NAD+ linked and FAD linked substrates. Respiratory control ratio, an index of membrane integrity and P/O ratio which is a measure of phosphorylation efficiency decreased significantly. There was a significant decrease in the activities of NADH dehydrogenase, succinate dehydrogenase and cytochrome oxidase. A significant decrease was also seen on membrane potential, cytochrome aa3, cytochrome b, cytochrome c and on phospholipids of mitochondria. The observed mitochondrial dysfunctions were related to increased lipid peroxidation, which could cause loss of membrane integrity and a decreased rate of phosphorylation. It is proposed that increased lipid peroxidation was responsible for the inhibition on both oxidation and phosphorylation in mitochondria in galactosamine treated rats.

Galactosamine [GaIN] inhibits luminol-dependent chemiluminescence of human polymorphonuclear leukocytes

The aim of the present study was to examine the effect of D- galactosamine HCl [GaIN] on the oxidative respiratory burst of isolated human polymorphonuclear leukocyte [PMNs]. GaIN added in vitro to PMNs caused a marked inhibitory effect on the luminol- dependent chemiluminescene [CL] induced by phorbol myristate acetate [PMA] on PMNs. The inhibitory effect produced by GaIN was both dose and time dependent when PMA was used to stimulate the oxidative burst of PMNs. The effect of GaIN on the isolated PMNs was partially irreversible, following washing of the GaIN-treated PMNs with phosphate buffered saline [PBS]. PMNs viability was not significantly altered by incubation with GaIN. Addition of lipopolysaccharide [endotoxin] to isolate PMNs in the presence or absence of GaIN did not alter the oxidative burst of PMNs. Addition of oxygen-free radical scavengers enhanced the inhibitory effect induced by GaIN on PMNs CL. In a cell free medium, GaIN has no inhibitory effect on CL induced by luminol, H2O2 and horse radish peroxidase. As a conclusion, results suggested that in vitro, GaIN has a remarkable inhibitory effect on the release of oxygen products from stimulated PMNs

Induction of tumour necrosis factor alpha in experimental animals treated with hepatotoxicants.

Administrations of hepatotoxicants namely carbon tetrachloride (CCl4:0.4 ml in 1.2 ml of liquid paraffin) and ANIT (1 ml of 1.5% solution in liquid paraffin) in Charles foster rats (force fed) and D-galactosamine (8 mg in water per swiss albino mouse, ip) induce the release of TNF-alpha in case of CCl4 and D-galactosamine. High TNF-alpha level was observed up to 48 hr in CCl4 and up to 24 hr in D-galactosamine treated animals. Elevated levels of biochemical like ALP and SGPT are also recorded. TNF-alpha level can be measured of tissue damage and prognosis in case of hepatitis.