Diosgenin Alleviates Neuropathic Pain Associated with Alterations in Spinal Mitochondrial and ER Stress-Related Factors in CCI Mice

Neuropathic pain is difficult to treat as current therapies are often insufficient and provide incomplete relief. However, the mechanisms of chronic nerve injury are poorly addressed. In the present study, we explored the therapeutic effects of natural steroidal saponin diosgenin and its possible spinal mechanisms in a mouse model of chronic constriction injury (CCI)-induced neuropathic pain. C57BL/6 mice underwent CCI and were orally administered diosgenin once daily from three days after surgery. Diosgenin significantly alleviated CCI-induced mechanical allodynia and thermal hyperalgesia and enhanced motor performance in paw withdrawal, open-field, and rotarod tests. These effects were associated with the restoration of mitochondrial homeostasis as evidenced by the increased mitochondrial fusion, decreased fission and activation of NRF2 signaling. Diosgenin also suppressed spinal endoplasmic reticulum (ER) stress, mitochondria apoptotic signaling and the expression of pro-inflammatory cytokines, and pain-related neuropeptides. Mechanistically, the inhibition of spinal NRF2 proteins and the pharmacological induction of ER stress reduced the analgesic effect of diosgenin, highlighting the critical involvement of these pathways in its therapeutic efficacy. Altogether, diosgenin alleviated neuropathic pain in CCI mice that were pharmacologically associated with the restoration of spinal mitochondrial function and ER stress suppression. Therefore, diosgenin could be a promising natural steroidal therapeutic candidate in alleviating neuropathic pain.