A Protective Role of Hydrogen Sulfide Donor GYY4137 Through Activated Microglia-induced Anti-inflammatory Cytokines in the Spinal Cord of Diabetic Rats.

The increasing significance of inflammation in the pathophysiology of diabetes and its complications, such as diabetic peripheral neuropathy, has generated significant interest in targeting inflammation for disease prevention and control. Hydrogen sulfide (H₂S) has emerged as a promising therapeutic candidate due to its regulatory role in neuroinflammation. The present study investigated the anti-inflammatory effects of prolonged treatment with H₂S donor GYY4137 on microglial and astrocyte activation, along with the subsequent release of anti-inflammatory cytokines, including interleukin (IL)-4, IL-10, IL-13, transforming growth factor-beta (TGF-β), and arginase-1, in the spinal cords of streptozotocin-induced diabetic male rats. We also examined the effect of GYY4137 on signal transducer and activator of transcription 3 (STAT3) and the expression of pro-inflammatory cytokine IL-12. STAT3 is crucial for cytokine release signaling and microglial polarization, while IL-12 is a key marker of inflammation severity in diabetes. GYY4137 treatment effectively suppressed microglial activation, STAT3 activation, and IL-12 expression, while significantly increasing the secretion of anti-inflammatory cytokines in diabetic rats during weeks 4, 8, and 10 post-treatments. Our previous work demonstrated that 4-week-GYY4137 treatment suppressed pro-inflammatory cytokines in diabetic rats. Here, we show that prolonged GYY4137 treatment facilitated microglial transition from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. The treatment also prevented the loss of astrocytes and neuronal cells in the spinal cord, indicating neuroprotective effects. In conclusion, our findings suggest that H₂S can shift microglial activity from neuroinflammation to neuroprotection, highlighting its potential as a possible candidate for novel therapeutic strategy for diabetes and its complications.