A Chemical Screen Identifies Novel Compounds That Overcome Glial-Mediated Inhibition of Neuronal Regeneration

Central nervous system (CNS) injuries often lead to permanent disabilities due to the limited ability of nerve fibers (axons) to regrow. This study aimed to identify chemical compounds that can promote axon regeneration despite the inhibitory environment created by myelin and glial scars. Researchers screened a novel library of triazine compounds for their ability to enhance neurite outgrowth from cerebellar neurons grown on myelin. This screen identified four compounds that showed promise in overcoming glial inhibition. One of the identified compounds, F05, was found to alter microtubule dynamics and increase microtubule density in both fibroblasts and neurons. Importantly, F05 promoted regeneration of dorsal column axons after acute lesions and enhanced optic nerve axon regeneration following nerve crush in vivo.

• 1
  A chemical screen identified four novel triazine compounds (A05, C05, F05, and H08) that overcome myelin-mediated inhibition of neurite outgrowth.
• 2
  The hit compounds increase neurite growth not only on myelin but also on CSPG substrates and on an in vitro model of glial scar, suggesting that they act on signaling nodes common to multiple inhibitory stimuli.
• 3
  Compound F05 alters microtubule dynamics by increasing microtubule density, and it promotes acute regeneration of dorsal column axons and potentiates regeneration of optic nerve axons in vivo.