Objectives: 

Exaggerated inflammatory response following disregulation of NF-kB signaling pathway has been implicated in several acute and chronic inflammatory diseases, including sepsis and septic shock. Despite this knowledge, effective treatment of these pathologies remain elusive, and research efforts have identified NF-kB pathway as a therapeutic target for sepsis. Herein, we evaluated whether the antioxidant and anti-inflammatory actions of melatonin may be related to the inhibition of the NF-kB-dependent immune innate response during sepsis.

Materials: 

C57BL/6J mice were grouped in control group, three groups of septic mice induced by cecal ligation and puncture and two groups of septic mice treated with 3 or 4 doses of melatonin, respectively. At 6, 8 and 24 hours after surgery or melatonin treatment, mice were sacrificed and heart collected and used to evaluate the expression and level of key molecules involved in NF-kB signaling pathway by RT-PCR and western-blot, respectively. The DNA-binding capacity NF-kB p65 subunit was assesses by ELISA. Finally, cytosolic oxidative stress was measured by spectrophotometric methods.

Results: 

A transient and time-dependent NF-kB activation was observed in septic mice, with peak levels between 6 and 8 h, and declining 24 h later. In spite of the NF-kB reduction at 24 h after sepsis, the proinflammatory and prooxidant status, and the proinflammatory cytokine levels remained elevated at this time. At both early late septic stages, melatonin treatment increased nuclear level and deacetylase activity of sirtuin-1, reducing nuclear translocation and DNA binding activity of NF-kB. Therefore, melatonin decreased the level and expression of NF-kB-dependent proinflammatory cytokines and restored redox balance in septic mice.

Conclusions: 

These results decode the anti-inflammatory activity of melatonin through a sirtuin-1-dependent pathway, providing experimental evidence for the therapeutic application of melatonin in the treatment of sepsis and other inflammatory disorders.