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Background Painful diabetic neuropathy (PDN) is a common complication of type 2 diabetes, characterized by neuropathic pain and inflammation. Its pathogenesis involves oxidative stress, inflammatory responses, and dysfunction of the spinal cord glymphatic system. This study aimed to investigate the protective effects of Ginkgolide B (GB) in alleviating PDN, with a particular focus on its roles in modulating the gut microbiota and enhancing glymphatic function in the spinal cord. Methods A PDN model was established in male Sprague–Dawley rats to evaluate the therapeutic effects of GB. GB was administered to assess its impact on gut microbiota composition, intestinal barrier integrity, and inflammation in both the intestine and spinal cord. Additionally, the effect of GB on aquaporin-4 (AQP4) polarization in the spinal cord glymphatic system was examined to determine its role in facilitating the clearance of inflammatory mediators. Results GB treatment significantly alleviated hallmark features of PDN, including neuropathic pain and spinal cord inflammation. It modulated the gut microbiota, restored intestinal barrier function, and reduced intestinal inflammation. Moreover, GB reestablished AQP4 polarity in the spinal cord, thereby enhancing glymphatic function and promoting the clearance of inflammatory mediators, which contributed to reduced neuroinflammation. Conclusion These findings suggest that Ginkgolide B may represent a multifaceted therapeutic strategy for PDN. By regulating the microbiota–gut–spinal cord glymphatic axis, improving glymphatic function, and alleviating PDN symptoms, GB shows promise as a novel treatment targeting both metabolic and neuroinflammatory components of the disease.
Jia et al. (Wed,) studied this question.