The Protective Effect of Ramelteon and in Combination with Dexamethasone on the Lipopolysaccharide-Induced Cytokine Storm in Mice.

Cytokine Storm Syndrome (CSs) is a potentially life threatening condition, characterized by robust elevated; of circulating pro-inflammatory cytokines; occurring after a hyperactive immune system. Is a well-known as a worldwide health problem, leading to multi-organ failure and death. Objectives: This study was carried out to investigate the protective role and probability of additive or synergistic anti-inflammatory activity; of ramelteon and in combination with dexamethasone on the lipopolysaccharide (LPS) induced "Cytokine Storm" on mice model and its potential regulatory mechanism(s). Methods: Sixty Swiss albino male mice of; (25 ± 5 grams; 8-12 weeks) had free access to food and water. After 2 weeks of adaptation, mice; randomly separated in five groups (n = 12): Group I, mice received (0.9% N/S i.p.); Group II, mice received (5 mg/kg i.p.) LPS only. Group III, mice received (2.5 mg/kg, i.p.) dexamethasone, Group IV, mice received (100 mg/kg i.p.) ramelteon, Group V, mice received half dose of dexamethasone+ ramelteon combination (1.25 mg/kg i.p +50 mg/kg i.p). For systematic inflammatory stimulation mimicking "cytokine storm" LPS; E. coli O55:B5 (5 mg/kg i.p.) was induced within one hr. After 48 h the effects of interventional agents and vehicle or LPS challenge; on lung, heart, liver, kidney histopathological changes, and levels of inflammatory cytokines: (IL-6, IL8, IL-1β, and TNF-α) in the serum were detected. Results: IL-1β, IL-6, IL8 and TNF-α elevated serum levels significantly reduced (P < 0.001) in all treatment group. Additionally, they ameliorated the histopathological changes induced by (LPS) and improving macroscopic scores (P < 0.001). Conclusion: In conclusion, ramelteon treatment had a diverse protective effects against "Cytokine Storm" with a mechanism based on attenuation serum levels of inflammatory cytokines (IL-1β, IL-6, IL-8 and TNF-α) and through reduction of histopathological damage during endotoxemia induced via LPS challenge on male mice model. RAM/DEX combination had superior advantage than an agent use alone probably via synergistic anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

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