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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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DNA / genetics
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Dose-Response Relationship, Drug
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Forelimb / physiology
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Hindlimb / physiology
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Hyperalgesia / drug therapy
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Immunohistochemistry
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Isoleucine / analogs & derivatives*
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Isoleucine / therapeutic use
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Locomotion / drug effects
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitogen-Activated Protein Kinase 10 / metabolism
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Morpholines / therapeutic use*
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Myelin Sheath / metabolism*
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Nerve Growth Factor / metabolism*
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Polymerase Chain Reaction
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Protein Precursors / metabolism*
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Receptor, Nerve Growth Factor / drug effects*
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Receptor, Nerve Growth Factor / metabolism*
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Spinal Cord Injuries / drug therapy*
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Spinal Cord Injuries / pathology
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Swimming / physiology
Substances
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LM11A-31
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Morpholines
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Protein Precursors
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Receptor, Nerve Growth Factor
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pro-nerve growth factor, mouse
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Isoleucine
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DNA
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Nerve Growth Factor
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Mitogen-Activated Protein Kinase 10