Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide‐induced multiple organ dysfunction syndrome in rats

Abstract

We evaluated the role of melatonin in endotoxemia caused by lipopolysaccharide (LPS) in unanesthetized rats. The expression of inducible isoform of nitric oxide synthase (iNOS) and the increase in the oxidative stress seem to be responsible for the failure of lungs, liver, and kidneys in endotoxemia. Bacterial LPS (10 mg/kg b. w) was i.v. injected 6 h before rats were killed and melatonin (10-60 mg/kg b.w.) was i.p. injected before and/or after LPS. Endotoxemia was associated with a significant rise in the serum levels of aspartate and alanine aminotransferases, gamma-glutamyl-transferase, alkaline phosphatase, creatinine, urea, and uric acid, and hence liver and renal dysfunction. LPS also increased serum levels of cholesterol and triglycerides and reduced glucose levels. Melatonin administration counteracted these organ and metabolic alterations at doses ranging between 20 and 60 mg/kg b. w. Melatonin significantly decreased lung lipid peroxidation and counteracted the LPS-induced NO levels in lungs and liver. Our results also show an inhibition of iNOS activity in rat lungs by melatonin in a dose-dependent manner. Expression of iNOS mRNA in lungs and liver was significantly decreased by melatonin (60 mg/kg b. w., 58-65%). We conclude that melatonin inhibits NO production mainly by inhibition of iNOS expression. The inhibition of NO levels may account for the protection of the indoleamine against LPS-induced endotoxemia in rats.

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

“…Melatonin displays important antioxidant properties based on its free radical scavenger ability [46,48,52,53] and, in contrast to conventional antioxidants, rapidly crosses the blood-brain barrier after systemic administration and reaches every neuronal compartment [41]. Melatonin also regulates the expression and activity of the redox enzymes [9,16]. Deprenyl shares with melatonin common features such as neuroprotective and antioxidant effects, and we recently reported a synergistic effects between both compounds against DA autoxidation in vitro [32].…”

“…Melatonin is a strong scavenger of free radicals [46,48] and regulates the activity and expression of antioxidant enzymes [9,37]. Melatonin reportedly protects cells, tissues and organs against oxidative damage caused by various free radical generating agents [5,16,17]. Melatonin also protects the brain against oxidative damage [3,47].…”

Superoxide as a Messenger of Endothelial Function

“…Increased • O 2 -production is unsuccessfully counter-balanced by the enhanced expression and activity of NO-synthesizing enzymes. At least in the chronic process of vascular aging, this directly involves eNOS but not iNOS, although in situations of acute oxidative stress, iNOS may also be induced (Crespo et al, 1999). PN nitrates an essential tyrosine residue in Mn-SOD with the participation of manganese catalysis.…”

Comparison of Effects of Nitric Oxide Synthase (NOS) Inhibitors on Plasma Nitrite/Nitrate Levels and Tissue NOS Activity in Septic Organs

“…It has been reported that iNOS-derived NO suppresses tissue damage in acute lung injury; it acts to block the generation of chemokines (23) or inhibits sepsis-induced pulmonary apoptosis (22). Thus, iNOS-derived NO has both a beneficial effect (defence against infectious Numerous studies have been done concerning the relationship between the benefits and costs of inhibiting NO production in septic models (5,10,26,28,30). A consensus among these studies is that non-selective NOS inhibitors cause excessive vasoconstriction by inhibiting eNOS, thus exacerbating organ ischemia.…”