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 2weeks of adaptation, mice; randomly separated in five groups (n =12): Group I, mice received (0.9% N\S i.p.); Group II, mice received (5mg\kg i.p.) LPS only .Group III, mice received (2.5mg/kg, i.p.) dexamethasone, Group IV, mice received (100mg/kg i.p.) ramelteon, Group V, mice received half dose of dexamethasone+ ramelteon combination (1.25 mg\kg i.p +50mg\kg i.p). For systematic inflammatory stimulation mimicking “cytokine storm” LPS; E. coli O55:B5 (5mg\kg i.p.) was induced within one hr. After 48h 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.