A chemical screen identifies novel compounds that overcome glial-mediated inhibition of neuronal regeneration.
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.
Usher
Lynn C
LC
Departments of Pharmacology, Neurological Surgery, and Ophthalmology, and Miami Project to Cure Paralysis, Neuroscience Program, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Johnstone
Andrea
A
Ertürk
Ali
A
Hu
Ying
Y
Strikis
Dinara
D
Wanner
Ina B
IB
Moorman
Sanne
S
Lee
Jae-Wook
JW
Min
Jaeki
J
Ha
Hyung-Ho
HH
Duan
Yuanli
Y
Hoffman
Stanley
S
Goldberg
Jeffrey L
JL
Bradke
Frank
F
Chang
Young-Tae
YT
Lemmon
Vance P
VP
Bixby
John L
JL
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D000242:Cyclic AMP / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D057166:High-Throughput Screening Assays; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000502:physiology; D009409:Nerve Crush; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D009900:Optic Nerve / Q000166:cytology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D013116:Spinal Cord / Q000166:cytology; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
D014227:Triazines; D000242:Cyclic AMP; D066246:ErbB Receptors; D011493:Protein Kinase C