Hypothesis / aims of study
Bladder dysfunction following spinal cord injury (SCI) severely compromises patients’ quality of life. Overactivated microglia after SCI intensify their interaction with astrocytes, leading to secondary injury. Glucagon-like peptide-1 receptor (GLP-1R) agonists have been previously verified to exert neuroprotective effects in neurodegenerative diseases. This study aims to investigate the improvement of neurogenic bladder by GLP-1R agonists (GLP-1RA) after spinal cord injury.
Study design, materials and methods
The effects and mechanisms of GLP-1R activation via Exendin-4 (Ex-4) were studied using in vitro models of primary neurons, primary neural stem cells, glial cells, and an SCI mouse model. Microglial polarization and neuroinflammatory levels were detected by Western blotting, flow cytometry, and immunofluorescence. Transwell assays demonstrated that Ex-4 treatment attenuated the neurotoxicity of M1 microglia and inhibited the transformation of reactive astrocytes. Spinal cord pathology, anterograde tracing of the raphe nucleus, retrograde tracing, and urodynamics in mice confirmed enhanced neuroplasticity and improved bladder function in SCI mice following Ex-4 administration.
Results
Flow cytometric analysis of LPS-induced microglia with or without treated Ex-4 showed a significant increase in the proportion of CD206(+)CD86(-) M2 microglia (13.6%vs45.3%, p value < 0.05). Spinal cord pathology and immunofluorescence revealed reduced neuroinflammation and neuronal death in the spinal cord of SCI mice treated with Ex-4. Compared with the SCI group, Ex-4-treated mice exhibited significant improvements in post-void residual (PVR) (0.2 mLvs0.5 mL, p value< 0.05), maximum detrusor pressure (75 cm H₂O vs 38 cm H₂O, p value< 0.05), and voiding efficiency (16%vs78%, p value < 0.05).
Interpretation of results
Activation of GLP-1R alleviates microglia-induced neuroinflammation by switching microglia from the M1 to the M2 phenotype. In mice, GLP-1R activation effectively attenuates SCI-induced neuronal death and preserves urinary function.