Dendrophenol Mitigates inflammatory sickness behavior and maintains CNS Function in Murine models

• Dendrophenol dose-dependently attenuates inflammatory sickness behaviors. • Dendrophenol suppresses key pro-inflammatory mediators (TNF-α, IL-6, IL-1β, MCP-1) in vivo and in vitro. • Dendrophenol maintains CNS safety without adverse neurological effects. Inflammatory sickness behaviors—characterized by reduced mobility, anhedonia, and social withdrawal—represent significant clinical manifestations of systemic inflammation and immune activation. This study evaluated the pharmacological effects and mechanism of action of dendrophenol, a bioactive compound from Dendrobium senile , in preclinical models of inflammatory disease. Male mice received dendrophenol (12.5, 25, 50 mg/kg, i.p.) in acute inflammation models (LPS-induced endotoxemia and formalin-induced inflammation). Pharmacological efficacy was assessed via behavioral phenotyping, inflammatory marker quantification, and CNS safety evaluation. Dendrophenol demonstrated dose-dependent attenuation of sickness behaviors in both LPS and formalin models. Mechanistic studies revealed that dendrophenol suppressed systemic and central pro-inflammatory mediators (TNF-α, IL-6, IL-1β, MCP-1) in vivo. Cellular mechanistic validation in LPS-stimulated macrophages and microglia demonstrated that dendrophenol inhibited inflammatory immune cell activation and cytokine release. Critically, dendrophenol produced no effects on locomotor activity and general behaviors, confirming CNS safety at all tested doses. These findings establish dendrophenol as a pharmacologically active anti-inflammatory compound with favorable safety characteristics, supporting preclinical validation for further drug development in inflammation-associated pathologies. The compound warrants advancement to dose-escalation and pharmacokinetic studies.