Abstract Background: Diabetes-related pathological alterations in body organs may take place due to immunological reactions and inflammatory/oxidative burden. Aim of Study: The current study aimed to test the neuropro-tective effect of topiramate in an animal model of peripheral di-abetic neuropathy (DN) and test its ability to suppress the spinal cord inflammatory burden and glial reactivity. Material and Methods: The study was carried out in Fac-ulty of Medicine, Suez Canal University, Male adult mice were assigned as vehicle group, DN group (alloxan 180mg/kg, i.p.), DN+topiramate 10-mg/kg and DN+topiramate 30-mg/kg. Mice received topiramate therapy for four weeks then tested for allo-dynia and hyperalgesia. Spinal cord specimens were examined by molecular assays, light microscopic technique and neurofila-ment heavy chain (NEFH) immunostaining Sciatic nerves were examined microscopically. Results: Indicated that DN mice had lower the hotplate la-tency time (0.46-fold of latency to licking) and lower the von-Frey test pain threshold (0.6-fold of filament size). In contrast, treatment with topiramate increased these values. Sciatic nerve showed axonal degeneration, demyelination, loss of some cen-tral axons, and shrunken Schwann cells. Further, spinal cords of DN mice had elevated levels of GFAP (5.6-fold) and lower GAP-43 (0.25-fold), inflammatory cytokines (-3 or 4-fold) and neuronal degeneration with dystrophic neurons. Conclusion: Topiramate produced neuroprotection and increased pain thresholds in mice with DN, suppressed spinal cord inflammation and GFAP but enhanced plasticity as indi-cated by higher GAP-43 protein level. Hence, our study rein-forces topiramate as neuroprotection and suggests it for allevi-ating neuropathic pain.