Journal
JOURNAL OF NEUROSCIENCE
Volume 33, Issue 2, Pages 397-410Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0399-12.2013
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Funding
- National Institute of Neurological Disorders and Stroke (NINDS) [RO1NS050585, R21NS059503, P30NS045758]
- Christopher and Dana Reeve Foundation
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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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