Sedanolide alleviates LPS‑induced depressive‑like behaviors by modulating the C3a/C3aR signaling axis and microglial glycolysis

A total of ~30% of patients with depression do not respond to pharmacological treatment.Sedanolide (SD) is a compound derived from Chinese medicinal herbs and has structural features associated with anti-inflammatory activity.However, its effect on depressive disorders remains unclear.The present study aimed to examine the therapeutic effects of SD in lipopolysaccharide (LPS)-induced depressive disorder and to investigate the underlying mechanisms.An LPS-induced male mouse model of depressive-like behavior was used to evaluate the therapeutic effect and underlying mechanisms of SD.The mRNA levels of pro-inflammatory cytokines and the activation state of microglia in the medial prefrontal cortex (mPFC) were assessed.In addition, high-throughput RNA sequencing was performed as an unbiased transcriptomic screen to identify differentially expressed genes.Western blotting and ELISA assays were then used to validate the expression and activation levels of key candidate molecules within the identified pathways.BV-2 cell line was utilized to assess the aerobic glycolysis in vitro by metabolic extracellular flux analysis.Finally, the selective C3aR antagonist SB290157 was administered to determine whether the effects of SD depended on the downstream C3a/C3aR signaling cascade.SD treatment significantly increased the sucrose preference and reduced immobility time in both the tail suspension test and the forced swimming test in LPS-treated mice.Mechanistically, SD attenuated LPS-induced neuroinflammation and microglial activation in the mPFC.High-throughput RNA sequencing identified C3 and matrix metalloproteinase-9 as key transcriptional targets potentially involved in the effects of SD.Crucially, both in vitro and in vivo ELISA assays revealed that SD directly suppressed complement C3 activation by inhibiting its proteolytic cleavage into the active C3a fragments.Furthermore, SD reduced abnormal microglial aerobic glycolysis and restored mitochondrial respiration in vitro.By contrast, pharmacological inhibition of C3aR completely abolished protective effects of SD on behavioral despair, anhedonia, neuroinflammation and metabolic reprogramming.These findings indicate that SD alleviates depressive-like behaviors.The C3a/C3aR signaling axis appears to play a critical role in mediating its anti-inflammatory and anti-glycolytic effects.