Abstract
Restoration of neuronal connectivity after lesion of the central nervous system, such as spinal cord injury, is one of the biggest challenges in modern medicine. In particular, the accumulation of axon growth inhibitory factors at the site of injury constitutes a major obstacle to structural and thus functional repair. We previously investigated a group of prenylflavonoids derived from hops for their capacity to promote neuroregeneration. We identified a molecule called ENDF1 that was very potent to enhance regrowth and branching of neurites from dorsal root ganglion neurons in culture on growth promoting substrates. In the present study, we investigated ENDF1’s capacity to promote regeneration of rat dorsal root ganglion neurons in vitro in the presence of three main components of the extracellular matrix acting as axon growth inhibitors: Semaphorin 3A, Ephrin A4 and mixed chondroitin sulfate proteoglycans. We report that ENDF1 application significantly promoted the percentages of sensory neurons able to regrow their neurites regardless of the presence of those inhibitors, and this to an extent similar to the one obtained after NGF treatment. Moreover, ENDF1 strongly enhanced the total neurite length and the complexity of neurites extending from neurons challenged with axon growth inhibitors. Although the impact of NGF and ENDF1 on the regeneration of neurons was similar, the activity of ENDF1 was not mediated by signaling through the TrkA receptor, indicating that each molecule act through different signaling pathways. In addition, ENDF1 did not decrease the phosphorylation of cofilin, a downstream effector of the regeneration-associated RhoA/ROCK signaling pathway. Hence, ENDF1 is a potent pro-neuroregenerative factors that could help in identifying new efficient targets for regenerative therapies of the nervous system.
Highlights
Many therapeutic interventions currently applied following spinal cord injury aim for a stabilization of the lesion and for a limitation of exacerbating secondary damages
We evaluated the ability of dorsal root ganglion (DRG) neurons to regrow their neurites on coverslips coated with 1 to 50 μg/mL chondroitin sulfate proteoglycans (CSPGs), or coated with ephrin A4 or semaphorin 3A in concentrations ranging from 1 to
We further addressed the potency of ENDF1 to promote regeneration of DRG neurons seeded on extracellular matrix (ECM) inhibitors-coated coverslips (i.e., 5 μg/mL CSPGs, 10 μg/mL ephrin A4, or 5 μg/mL semaphorin 3A)
Summary
Many therapeutic interventions currently applied following spinal cord injury aim for a stabilization of the lesion and for a limitation of exacerbating secondary damages These interventions, cannot re-establish lost neuronal connectivity which would be crucial for functional regeneration. Ephrin A4 receptors (ephA4) become rapidly upregulated at the lesion site, promoting astrogliosis and loss of neurite regrowth (Fabes et al, 2006; Frugier et al, 2012) Both semaphorins and ephrins are major chemorepellent axon guidance molecules present in the ECM and their accumulation at the lesion site provokes the collapse of growth cone from regenerating axons (Rohm et al, 2000; Lisabeth et al, 2013). We investigated the capacity of ENDF1 to promote regeneration of rat DRG neurons in the presence of ECM axonal growth inhibitors known to accumulate at the CNS lesion sites
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