A chemical screen identifies novel compounds that overcome glial-mediated inhibition of neuronal regeneration.

Abstract

A major barrier to regeneration of CNS axons is the presence of growth-inhibitory proteins associated with myelin and the glial scar. To identify chemical compounds with the ability to overcome the inhibition of regeneration, we screened a novel triazine library, based on the ability of compounds to increase neurite outgrowth from cerebellar neurons on inhibitory myelin substrates. The screen produced four "hit compounds," which act with nanomolar potency on several different neuronal types and on several distinct substrates relevant to glial inhibition. Moreover, the compounds selectively overcome inhibition rather than promote growth in general. The compounds do not affect neuronal cAMP levels, PKC activity, or EGFR (epidermal growth factor receptor) activation. Interestingly, one of the compounds alters microtubule dynamics and increases microtubule density in both fibroblasts and neurons. This same compound promotes regeneration of dorsal column axons after acute lesions and potentiates regeneration of optic nerve axons after nerve crush in vivo. These compounds should provide insight into the mechanisms through which glial-derived inhibitors of regeneration act, and could lead to the development of novel therapies for CNS injury.

• Authors: Lynn C Usher, Andrea Johnstone, Ali Ertürk, Ying Hu, Dinara Strikis, Ina B Wanner, Sanne Moorman, Jae-Wook Lee, Jaeki Min, Hyung-Ho Ha, Yuanli Duan, Stanley Hoffman, Jeffrey L Goldberg, Frank Bradke, Young-Tae Chang, Vance P Lemmon, John L Bixby
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 30 Issue 13 Pg. 4693-706 (Mar 31 2010) ISSN: 1529-2401 [Electronic] United States
• PMID: 20357120 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Triazines
• Cyclic AMP
• ErbB Receptors
• Protein Kinase C

Topics

• Animals
• Axons (drug effects, physiology)
• Cells, Cultured
• Cerebellum (cytology)
• Cerebral Cortex (cytology)
• Cyclic AMP (metabolism)
• ErbB Receptors (metabolism)
• Fibroblasts (drug effects, physiology)
• High-Throughput Screening Assays
• Mice
• Mice, Inbred C57BL
• Myelin Sheath (physiology)
• Nerve Crush
• Neurites (drug effects, physiology)
• Neuroglia (physiology)
• Neurons (drug effects, physiology, ultrastructure)
• Optic Nerve (cytology)
• Protein Kinase C (metabolism)
• Rats
• Rats, Sprague-Dawley
• Regeneration
• Spinal Cord (cytology)
• Triazines (chemistry, pharmacology)