Astaxanthin alleviates spinal nerve ligation-induced neuropathic pain by modulating propionic acid levels

The treatment for neuropathic pain (NP) remains challenging. Propionic acid (PA), derived from gut microbiota, is a promising therapeutic target for NP. However, the precise role of PA in NP is nebulous; further, whether Astaxanthin (AST), which exhibits analgesic properties, is involved in regulating PA in NP remains unknown.

We explored the role of PA in NP development and whether AST relieves NP by modulating PA levels; further, we identified novel therapeutic strategies for NP.

The L4 spinal nerve was ligated (SNL) to establish a mouse model of NP. The composition of the gut microbiota was analysed through 16S rRNA sequencing. PA in faeces, blood, and spinal cord were quantitatively measured using gas chromatography-tandem mass spectrometry (GC-MS). Network pharmacology was used to identify therapeutic targets of PA for NP. The interactions between PA and its targets were analysed using molecular docking, molecular dynamics simulations, quantitative real-time polymerase chain reaction, and western blot.

Analysis of faecal samples from SNL mice showed dysregulation in the gut microbiota and alterations in PA metabolism-related enzymes. GC-MS analysis revealed reduced PA levels in faeces, serum, and spinal cord tissue. Network pharmacology and molecular docking identified therapeutic targets shared between PA and NP, primarily related to inflammation regulation. Treatment with exogenous PA supplementation alleviated pain and inhibited inflammation in the intestine and spinal cord, including NLRP3 inflammasome and NF-κB activation.

AST treatment modulated the gut microbiota, elevated PA levels, reduced inflammation, and strengthened the intestinal barrier, exerting an analgesic effect. Enhancing the levels of PA is a potentially novel mechanism underlying the analgesic effects of AST.