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: 6.34). 01/2013; 33(2):397-410. DOI: 10.1523/JNEUROSCI.0399-12.2013
Source: PubMed


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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    • "p75NTR and TrkA signaling stimulated by NGF binding are essential for BFCN function and survival, and this signaling is disrupted in AD brains [49], . Furthermore, degenerative signaling is augmented in AD due, in part, to increased p75NTR/Trk ratios [52], [53], [54], elevated proNGF levels [15], [55], [56], [57], and Aβ interactions either directly and/or indirectly with p75NTR [58]. LM11A-31 competes with NGF and proNGF binding to p75NTR but not TrkA [12], [15] and has a signaling profile that is distinct from NGF [12]. "
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    ABSTRACT: Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.
    PLoS ONE 08/2014; 9(8):e102136. DOI:10.1371/journal.pone.0102136 · 3.23 Impact Factor
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    • "More recently a study has shown that by interfering with the interaction between proNGF and p75 using a small, non-peptide, molecule named LM11A-3 prevented OL loss, increased the number of myelinating axons and improved functional recovery in an experimental model of SCI. Importantly this molecule can cross the blood-brain barrier without obvious toxicity complications (Tep et al., 2013). "
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    ABSTRACT: Spinal cord injury (SCI) is a major health burden and currently there is no effective medical intervention. Research performed over the last decade revealed that cells surrounding the central canal of the adult spinal cord and forming the ependymal layer acquire stem cell properties either in vitro or in response to injury. Following SCI activated ependymal cells generate progeny cells which migrate to the injury site but fail to produce the appropriate type of cells in sufficient number to limit the damage, rendering this physiological response mainly ineffective. Research is now focusing on the manipulation of ependymal cells to produce cells of the oligodendrocyte lineage which are primarily lost in such a situation leading to secondary neuronal degeneration. Thus, there is a need for a more focused approach to understand the molecular properties of adult ependymal cells in greater detail and develop effective strategies for guiding their response during SCI.
    Frontiers in Physiology 11/2013; 4:340. DOI:10.3389/fphys.2013.00340 · 3.53 Impact Factor
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    ABSTRACT: The p75 neurotrophin receptor (p75(NTR)) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75(NTR) ligands that inhibited amyloid-β-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75(NTR) ligand, LM11A-31, was administered orally to the Thy-1 hAPP(Lond/Swe) (APP(L/S)) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APP(L/S) mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75(NTR) is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.
    Neurobiology of aging 03/2013; 34(8). DOI:10.1016/j.neurobiolaging.2013.02.015 · 5.01 Impact Factor
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