Study summary · research use only
Semax peptide targets the μ opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this study using female C57BL/6 mice with spinal cord injury (SCI) at T9-T10, researchers examined the synthetic heptapeptide Semax, described as comprising the ACTH (4-7) fragment plus a C-terminal Pro-Gly-Pro tripeptide. Using histochemical methods, footprint analysis, Basso scores, inclined plane tests, molecular assays in SCI mice and a PC12 cell neuroinflammation model, plus RNA sequencing and network pharmacology, the study reports Semax was associated with improved functional recovery and reduced lysosomal-membrane-permeabilization-related pyroptosis via lowered oxidative stress. Semax was reported to regulate the protease USP18, confirmed by USP18 knockdown, and network pharmacology and docking identified the μ-opioid receptor as a target, linked to deubiquitination of the FTO protein.
Abstract
Lysosomal membrane permeabilization (LMP) is exacerbated following spinal cord injury (SCI), leading to increased neuronal cell death. Ubiquitination may affect LMP by regulating the stability and functionality of lysosomal membranes. Semax, a synthetic heptapeptide, comprising the ACTH (4-7) fragment and a C-terminal Pro-Gly-Pro tripeptide, exhibits neuroprotective properties and improves cognitive function. Given the key roles of LMP and ubiquitination in SCI pathophysiology, this study investigated how Semax could modulate these pathways to affect functional recovery following SCI. An SCI mouse model was generated by impacting the spinal cord of female C57BL/6 mice at T9-T10. Functional recovery in SCI mice was evaluated using histochemical methods, along with footprint analysis, Basso scores and inclined plane tests. Marker levels and distributions in the SCI model and in the PC12 cell neuroinflammation model were analysed using immunofluorescence, Western blot, RT-qPCR and transmission electron microscopy. RNA sequencing, network pharmacology and molecular docking were used to identify possible molecular targets of Semax. Semax improved SCI functional recovery and inhibited LMP-related pyroptosis in SCI mice and neuroinflammation models, by decreasing oxidative stress. RNA-seq and other analyses found that Semax regulated the ubiquitin specific protease USP18. USP18 knockdown confirmed Semax's role in SCI recovery. Network pharmacology and docking revealed the μ-opioid receptor as a Semax target. Semax promoted SCI functional recovery by targeting μ-opioid receptors, which regulated USP18 and, subsequently, deubiquitination of the fat mass and obesity-associated protein (FTO), suggesting its potential for SCI treatment.
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