Document Detail


Oral administration of a small molecule targeted to block proNGF binding to p75 promotes myelin sparing and functional recovery after spinal cord injury.
MedLine Citation:
PMID:  23303920     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The lack of effective therapies for spinal cord injury points to the need for identifying novel targets for therapeutic intervention. Here we report that a small molecule, LM11A-31, developed to block proNGF-p75 interaction and p75-mediated cell death crosses the blood-brain barrier efficiently when delivered orally. Administered starting 4 h postinjury, LM11A-31 promotes functional recovery without causing any toxicity or increased pain in a mouse model of spinal contusion injury. In both weight-bearing open-field tests and nonweight-bearing swim tests, LM11A-31 was effective in improving motor function and coordination. Such functional improvement correlated with a >50% increase in the number of surviving oligodendrocytes and myelinated axons. We also demonstrate that LM11A-31 indeed inhibits proNGF-p75 interaction in vivo, thereby curtailing the JNK3-mediated apoptotic cascade. These results thus highlight p75 as a novel therapeutic target for an orally delivered treatment for spinal cord injury.
Authors:
Chhavy Tep; Tae Hee Lim; Pyung On Ko; Sami Getahun; Jae Cheon Ryu; Virginia M Goettl; Stephen M Massa; Michele Basso; Frank M Longo; Sung Ok Yoon
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  33     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-10     Completed Date:  2013-03-04     Revised Date:  2014-03-14    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  397-410     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
DNA / genetics
Dose-Response Relationship, Drug
Forelimb / physiology
Hindlimb / physiology
Hyperalgesia / drug therapy
Immunohistochemistry
Isoleucine / analogs & derivatives*,  therapeutic use
Locomotion / drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / drug effects,  metabolism
Mitogen-Activated Protein Kinase 10 / metabolism
Morpholines / therapeutic use*
Myelin Sheath / metabolism*
Nerve Growth Factor / metabolism*
Polymerase Chain Reaction
Protein Precursors / metabolism*
Receptor, Nerve Growth Factor / drug effects*,  metabolism*
Spinal Cord Injuries / drug therapy*,  pathology
Swimming / physiology
Grant Support
ID/Acronym/Agency:
P30NS045758/NS/NINDS NIH HHS; R01 NS050585/NS/NINDS NIH HHS; R01NS050585/NS/NINDS NIH HHS; R21 NS059503/NS/NINDS NIH HHS; R21NS059503/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/LM11A-31; 0/Morpholines; 0/Protein Precursors; 0/Receptor, Nerve Growth Factor; 0/pro-nerve growth factor, mouse; 04Y7590D77/Isoleucine; 9007-49-2/DNA; 9061-61-4/Nerve Growth Factor; EC 2.7.1.-/Mitogen-Activated Protein Kinase 10
Comments/Corrections
Erratum In:
J Neurosci. 2014 Jan 29;34(5):2012

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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