Scorpion Venom Heat-Resistant Synthetic Peptide Alleviates DSS-Induced Colitis via α7nAChR-Mediated Modulation of the JAK2/STAT3 Pathway

TL;DR

A synthetic peptide from scorpion venom reduces colitis symptoms by targeting a brain-gut inflammation pathway.

Contribution

SVHRSP is a novel neuroactive peptide shown to alleviate intestinal inflammation via α7nAChR-mediated JAK2/STAT3 activation.

Findings

SVHRSP reduced inflammation, repaired gut damage, and restored barrier function in colitis models.

The peptide's effects were blocked in α7nAChR knockout mice, showing receptor dependency.

SVHRSP suppressed proinflammatory cytokines by activating JAK2/STAT3 signaling in macrophages.

Abstract

Background: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder with limited treatment options. Emerging evidence reveals bidirectional crosstalk between gut and brain through inflammatory signaling, leading us to hypothesize that anti-neuroinflammatory agents may concurrently ameliorate intestinal inflammation. The scorpion venom-derived heat-resistant synthetic peptide (SVHRSP), a bioactive peptide initially identified in scorpion venom and subsequently synthesized by our laboratory, possesses neuroprotective, anti-inflammatory, and antioxidative activities. Its properties make SVHRSP a promising candidate for investigating the therapeutic potential of anti-neuroinflammatory strategies in mitigating intestinal inflammation. Methods: Using a chronic dextran sodium sulfate (DSS)-induced colitis model in wild-type and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice, along with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, we assessed SVHRSP’s effects on inflammation, histopathology, gut permeability, oxidative stress markers, and α7nAChR-Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling. Results: SVHRSP treatment significantly ameliorated colitis symptoms in wild-type mice by reducing inflammation, repairing histological damage, restoring gut barrier function, and attenuating oxidative stress, with these effects abolished in α7nAChR knockout mice. Mechanistically, SVHRSP activated JAK2/STAT3 signaling through α7nAChR engagement, suppressing proinflammatory cytokine production in macrophages. Conclusion: These results demonstrated that SVHRSP alleviated intestinal inflammation via α7nAChR-dependent JAK2/STAT3 activation. Combined with its known neuroprotective properties, our findings support the repurposing of this neuroactive peptide, SVHRSP, for treating intestinal inflammatory disorders.

Figures