Semax Promoted Spinal Cord Injury Recovery in Mice by Targeting Opioid Receptors | Research

The takeaway

The peptide Semax improved functional recovery after spinal cord injury in mice by targeting μ-opioid receptors and reducing lysosomal membrane damage and inflammatory cell death.

μ-opioid receptor target
Network pharmacology and molecular docking identified the μ-opioid receptor as Semax's molecular target for spinal cord injury protection

What the researchers found

Semax improved functional recovery in a mouse spinal cord injury model, as measured by footprint analysis, Basso locomotor scores, and inclined plane tests. The mechanism was traced through a novel pathway:

1. Semax targets the μ-opioid receptor (Oprm1)

2. This regulates the ubiquitin-specific protease USP18

3. USP18 controls deubiquitination of the FTO protein (fat mass and obesity-associated protein)

4. This stabilizes lysosomal membranes, reducing lysosomal membrane permeabilization (LMP)

5. Reduced LMP prevents pyroptosis (inflammatory cell death)

RNA sequencing, network pharmacology, and molecular docking confirmed the μ-opioid receptor as Semax's molecular target. USP18 knockdown experiments validated its role in the pathway.

Why it matters

Spinal cord injury remains one of the most devastating and treatment-resistant neurological conditions. This study identifies a completely new mechanism for Semax — a peptide already used clinically in Russia for stroke — connecting it to opioid receptor signaling and lysosomal stability. The discovery that Semax prevents inflammatory cell death through this pathway suggests it could be repurposed for spinal cord injury, an indication with very few effective treatments.

How the study worked

Researchers created spinal cord injuries in female C57BL/6 mice by impact at T9-T10. Functional recovery was assessed using footprint analysis, Basso locomotor scores, inclined plane tests, and histochemistry. Molecular mechanisms were investigated using immunofluorescence, Western blot, RT-qPCR, and transmission electron microscopy in both the SCI mouse model and a PC12 cell neuroinflammation model. RNA sequencing identified differentially expressed genes, network pharmacology predicted drug targets, and molecular docking confirmed receptor binding. USP18 knockdown experiments validated the proposed mechanism.

What this study cannot tell us

Only female mice were studied, and sex differences in spinal cord injury recovery are well documented. The mouse SCI model (contusion at T9-T10) represents only one type of spinal cord injury. Network pharmacology and molecular docking provide computational predictions that, while validated by knockdown experiments, may not capture the full complexity of in vivo drug-receptor interactions. Translation from mouse to human spinal cord injury has historically been very difficult.

How to read the evidence

This is a well-designed preclinical study in mice combining functional assessments with detailed mechanistic investigation using multiple molecular techniques. While the evidence for the proposed mechanism is strong, no human data exists for this application.

When this study was published

Published in 2025, this is a very recent study that reveals a new mechanism and potential application for the Semax peptide.

The bigger picture

This study adds spinal cord injury to the growing list of neurological conditions where Semax shows protective effects, alongside stroke and cognitive impairment. The identification of the μ-opioid receptor as a molecular target is particularly interesting because it connects Semax to the endogenous opioid system in a neuroprotective (rather than analgesic) context. The lysosomal membrane permeabilization pathway is also gaining recognition as a critical mechanism in neurological damage, making it an attractive therapeutic target.

Questions still open

Would Semax show similar protective effects in male mice and in different types of spinal cord injury models?
Does the μ-opioid receptor mechanism also underlie Semax's previously established neuroprotective effects in stroke?
Could Semax be combined with standard acute SCI treatments (like methylprednisolone) for enhanced recovery?

Common questions

How does Semax protect the spinal cord after injury?

This study found Semax works through a chain of molecular events: it activates μ-opioid receptors, which regulate a protein called USP18, which in turn stabilizes the membranes of lysosomes (cellular waste disposal units). When lysosomes are damaged in spinal cord injury, they leak and trigger inflammatory cell death. By keeping lysosomes intact, Semax prevents this destructive cascade and allows more neurons to survive.

Is Semax used to treat spinal cord injuries in people?

Not yet. Semax is approved in Russia for treating stroke and cognitive problems, but its use for spinal cord injury is purely experimental at this stage. This mouse study provides the scientific rationale for exploring this application, but human clinical trials would be needed before it could be used for SCI patients.

Read the original research

Semax peptide targets the μ opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice.

British journal of pharmacology, 182(22), 5489-5516

View on PubMed ↗Publisher’s paper ↗

Citation

Liu, Rongjie; Chen, Yituo; Huang, Haosheng; Li, Xiang; Lv, Junlei; Jiang, Liting; Jiang, Hongyi; Wu, Chenyu; Chen, Weikai; Xu, Hongwei; Zhu, Zhefan; Cai, Haoxu; Xiao, Jian; Yin, Lihui; Ni, Wenfei. (2025). Semax peptide targets the μ opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice.. British journal of pharmacology, 182(22), 5489-5516. https://doi.org/10.1111/bph.70122