Oral Administration of a Small Molecule Targeted to Block proNGF Binding to p75 Promotes Myelin Sparing and Functional Recovery after Spinal Cord Injury

Departments of Molecular and Cellular Biochemistry, and Physical Therapy, and Biochemistry Program, The Ohio State University, Columbus, Ohio 43210, Department of Neurology, University of California at San Francisco, San Francisco, California 94121, and Department of Neurology and Neurological Science, Stanford University, Stanford, California 94305.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 01/2013; 33(2):397-410. DOI: 10.1523/JNEUROSCI.0399-12.2013
Source: PubMed

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.

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