Introduction: Spinal cord injury (SCI) often results in anatomically incomplete damage, leaving some neural fibers spared but functionally compromised. Enhancing the function of these spared fibers, such as by promoting neuronal excitability, has shown promise, but therapeutic efficacy remains variable. Given observed demyelination in both human SCI patients and animal models, we hypothesized that enhancing myelination could improve conduction and functional recovery. Oligodendrocyte progenitor cells (OPCs) differentiate into oligodendrocytes, which generate myelin. Inhibiting GPR17, a G-protein coupled receptor known to restrict oligodendrocyte differentiation, has been shown to promote remyelination in the optic nerve crush injury model. However, the role of GPR17 inhibition in functional recovery after SCI remains unknown.
Methods: To explore this, we tested montelukast, an FDA-approved GPR17 inhibitor, in adult mice following T8 lateral hemisection SCI. Montelukast was administered post-injury, and locomotor function was assessed using the irregular ladder walk test over 56 days. Kinematic data were analyzed through principal component analysis (PCA) using DeepLabCut to compare montelukast-treated SCI mice with untreated SCI and control mice. Additionally, GPR17-/- mice were tested to confirm the role of GPR17, with and without montelukast treatment. Lineage tracing using PDGRF⍺-CreERT mice was conducted to evaluate the production of new oligodendrocytes.
Results: Our results showed that montelukast treatment significantly improved locomotor function in SCI mice, with PCA revealing movement patterns more similar to controls compared to untreated SCI mice. GPR17-/- mice also demonstrated improved locomotor performance, and montelukast treatment did not yield further benefits in these mice, confirming that montelukast acts through GPR17 inhibition. Furthermore, lineage tracing revealed that both montelukast treatment and GPR17 knockout increased the generation of new oligodendrocytes.
Conclusion : These findings suggest that targeting GPR17 through montelukast promotes oligodendrocyte differentiation and myelination, improving functional recovery in SCI. This study highlights the potential of montelukast as a novel pro-myelination therapeutic approach for spinal cord injury.
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