title: Oral administration of a small molecule targeted to block proNGF binding to p75 promotes myelin sparing and functional recovery after spinal cord injury.
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.
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Chhavy
authors.initials: C
authors.lastname: Tep
authors.forename: Tae Hee
authors.initials: TH
authors.lastname: Lim
authors.forename: Pyung On
authors.initials: PO
authors.lastname: Ko
authors.forename: Sami
authors.initials: S
authors.lastname: Getahun
authors.forename: Jae Cheon
authors.initials: JC
authors.lastname: Ryu
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Goettl
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Massa
authors.forename: Michele
authors.initials: M
authors.lastname: Basso
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Yoon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005552:Forelimb / Q000502:physiology; D006614:Hindlimb / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy; D007150:Immunohistochemistry; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism; D009025:Morpholines / Q000627:therapeutic use*; D009186:Myelin Sheath / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011498:Protein Precursors / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor / Q000187:drug effects* / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology; D013550:Swimming / Q000502:physiology
chemical_list: C575077:LM11A-31; D009025:Morpholines; D011498:Protein Precursors; D020800:Receptor, Nerve Growth Factor; C489226:pro-nerve growth factor, mouse; D007532:Isoleucine; D004247:DNA; D020932:Nerve Growth Factor; D048057:Mitogen-Activated Protein Kinase 10