Oral Administration of a Small Molecule Targeted to Block proNGF Binding to p75 Promotes Myelin Sparing and Functional Recovery after Spinal Cord Injury
- Chhavy Tep1,3,
- Tae Hee Lim1,
- Pyung On Ko1,
- Sami Getahun1,
- Jae Cheon Ryu1,
- Virginia M. Goettl1,
- Stephen M. Massa4,
- Michele Basso2,
- Frank M. Longo5, and
- Sung Ok Yoon1
- 1Departments of Molecular and Cellular Biochemistry, and
- 2Physical Therapy, and
- 3Biochemistry Program, The Ohio State University, Columbus, Ohio 43210,
- 4Department of Neurology, University of California at San Francisco, San Francisco, California 94121, and
- 5Department of Neurology and Neurological Science, Stanford University, Stanford, California 94305
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Author contributions: C.T. and S.O.Y. designed research; C.T., T.H.L., P.O.K., S.G., J.C.R., and V.M.G. performed research; S.M.M. and M.B. contributed unpublished reagents/analytic tools; C.T., F.M.L., and S.O.Y. analyzed data; C.T., F.M.L., and S.O.Y. wrote the paper.
Abstract
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.
- Received January 27, 2012.
- Revision received October 16, 2012.
- Accepted October 18, 2012.
- Copyright © 2013 the authors 0270-6474/13/330397-14$15.00/0
