Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro‐/anti‐inflammatory cytokine network, protection against oxidative damage and anti‐apoptotic effects

Abstract

Septic shock, the most severe problem of sepsis, is a lethal condition caused by the interaction of a pathogen-induced long chain of sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. The lethal effects of septic shock are associated with the production and release of numerous pro-inflammatory biochemical mediators including cytokines, nitric oxide and toxic oxygen and nitrogen radicals, together with development of massive apoptosis. As melatonin has remarkable properties as a cytokine modulator, antioxidant and anti-apoptotic agent, the present study was designed to evaluate the possible protective effect of melatonin against LPS-induced septic shock in Swiss mice. We observed that intraperitoneally (i.p.) administered-melatonin (10 mg/kg) 30 min prior, and 1 hr after i.p. LPS injection (0.75 mg/animal) markedly protected mice from the LPS lethal effects with 90% survival rates for melatonin and 20% for LPS-injected mice after 72 hr. The melatonin effect was mediated by modulating the release of pro-/anti-inflammatory cytokine levels, protection from oxidative damage and counteracting apoptotic cell death. Melatonin was able to partially counteract the increase in LPS-induced pro-inflammatory cytokine levels such as tumor necrosis factor-alpha, IL-12 and interferon-gamma at the local site of injection, while it increased the production of the anti-inflammatory cytokine IL-10 both locally and systemically. Furthermore, melatonin inhibited the LPS-induced nitrite/nitrate and lipid peroxidation levels in brain and liver and counteracted the sepsis-associated apoptotic process in spleen. In conclusion, we have demonstrated that melatonin improves the survival of mice with septic shock via its pleiotropic functions as an immunomodulator, antioxidant and anti-apoptotic mediator.

Melatonin treatment in old mice enables a more youthful response to LPS in the brain

“…Many of the gene changes described here are consistent with the observations that injection of LPS is more lethal for old mice than for young (Saito et al, 2003), and that survival is increased by melatonin, at least in young animals (Carrillo-Vico et al, 2005). The issue as to how gene expression patterns may be consistent with, or in some cases contradictory to, the mortality data is now discussed.…”

“…injection of LPS (Saito et al, 2003). Melatonin also increases the survival rate of young mice injected with an otherwise lethal dose of LPS (Carrillo-Vico et al, 2005). The age-related decline in amplitude of circadian melatonin secretion is especially pronounced in aged demented subjects and the decline of its nocturnal peak is correlated with the severity of cognitive impairment (Magri et al, 2004).…”

Melatonin: A pleiotropic molecule regulating inflammation

“…It was demonstrated that nitric oxide (NO) plays an important role in septic shock, an acute inflammatory response [134]. Indeed, melatonin improves the survival of mice with LPS-induced shock by -11 -reducing NO synthesis via its antioxidant and anti-apoptotic properties [135]. It was demonstrated that antioxidant treatment improves respiratory syncytial virus (RSV)-induced pulmonary inflammation.…”

Melatonin – a pleiotropic molecule involved in pathophysiological processes following organ transplantation

“…37 In murine septic shock models, melatonin supplementation has been reported to increase survival by down-regulating pro-inflammatory cytokines and also lipid peroxidation levels in the brain. 38 …”