Cobrotoxin Alleviates Lipopolysaccharide-Induced Depression-like Behavior in mice

Depression is a debilitating psychiatric disorder closely linked to neuroinflammation. Cobrotoxin (CoTX), an active component of Naja atra venom, exhibits multiple therapeutic effects, including analgesic, anti-inflammatory, and microcirculation-improving properties. However, its role in neuroinflammation-associated depression remains unexplored. This study investigated the effects of CoTX on lipopolysaccharide (LPS)-induced depression-like behavior in mice and underlying mechanisms. Our results demonstrated that CoTX treatment significantly ameliorated LPS-induced depression-like behaviors, as shown by increased sucrose preference in the sucrose preference test (SPT) and reduced immobility time in the forced swim test (FST) and tail suspension test (TST). Notably, the antidepressant-like effects of CoTX were not attributable to enhanced locomotor activity, as CoTX did not reverse LPS-induced hypolocomotion in the open field test (OFT). Histological analysis via Nissl staining revealed that CoTX increased the density of viable neurons in the hippocampal CA1, CA3, and dentate gyrus (DG) regions. Furthermore, CoTX suppressed LPS-induced microglial overactivation in the hippocampus, as reflected by reduced IBA-1-positive cell area and altered microglial morphology. Mechanistically, CoTX downregulated the mRNA expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IFN-γ) in the mouse cerebral cortex. In vitro studies using BV-2 microglial cells confirmed that CoTX inhibited LPS-induced expression of TNF-α, IL-6, and IL-1β while restoring the levels of the anti-inflammatory marker CD206, without affecting cell viability. Notably, CoTX exerted its anti-neuroinflammatory and antidepressant-like effects by suppressing the NF-κB signaling pathway, while had no effect on STAT3 phosphorylation. Collectively, our findings indicate that CoTX alleviates LPS-induced depression-like behaviors by inhibiting microglial activation and neuroinflammation possibly involving the NF-κB pathway, highlighting its therapeutic potential for inflammation-associated depression.