Stephen M Massa

University of California, San Francisco, San Francisco, California, United States

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Publications (66)324.51 Total impact

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    ABSTRACT: The valine 66 to methionine (Met) polymorphism within the brain-derived neurotrophic factor (BDNF) sequence reduces activity-dependent BDNF release and is associated with psychiatric disorders in humans. Alcoholism is one of the most prevalent psychiatric diseases. Here, we tested the hypothesis that this polymorphism increases the severity of alcohol abuse disorders. We generated transgenic mice carrying the mouse homolog of the human Met66BDNF allele (Met68BDNF) and used alcohol-drinking paradigms in combination with viral-mediated gene delivery and pharmacology. We found that Met68BDNF mice consumed excessive amounts of alcohol and continued to drink despite negative consequences, a hallmark of addiction. Importantly, compulsive alcohol intake was reversed by overexpression of the wild-type valine68BDNF allele in the ventromedial prefrontal cortex of the Met68BDNF mice or by systemic administration of the tropomyosin receptor kinase B agonist, LM22A-4. Our findings suggest that carrying this BDNF allele increases the risk of developing uncontrolled and excessive alcohol drinking that can be reversed by directly activating the BDNF receptor, tropomyosin receptor kinase B. Importantly, this work identifies a potential therapeutic strategy for the treatment of compulsive alcohol drinking in humans carrying the Met66BDNF allele. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Biological psychiatry 06/2015; DOI:10.1016/j.biopsych.2015.06.007 · 10.26 Impact Factor
  • Amy Friesland · Zhiying Weng · Maria Duenas · Stephen M Massa · Frank M Longo · Qun Lu ·
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    ABSTRACT: Cisplatin is an effective and widely used first-line chemotherapeutic drug for treating cancers. However, many patients sustain cisplatin-induced peripheral neuropathy (CIPN), often leading to a reduction in drug dosages or complete cessation of treatment altogether. Therefore, it is important to understand cisplatin mechanisms in peripheral nerve tissue mediating its toxicity and identify signaling pathways for potential intervention. Rho GTPase activation is increased following trauma in several models of neuronal injury. Thus, we investigated whether components of the Rho signaling pathway represent important neuroprotective targets with the potential to ameliorate CIPN and thereby optimize current chemotherapy treatment regimens. We have developed a novel CIPN model in the mouse. Using this model and primary neuronal culture, we determined whether LM11A-31, a small-molecule, orally bioavailable ligand of the p75 neurotrophin receptor (p75(NTR)), can modulate Rho GTPase signaling and reduce CIPN. Von Frey filament analysis of sural nerve function showed that LM11A-31 treatment prevented decreases in peripheral nerve sensation seen with cisplatin treatment. Morphometric analysis of harvested sural nerves revealed that cisplatin-induced abnormal nerve fiber morphology and the decreases in fiber area were alleviated with concurrent LM11A-31 treatment. Cisplatin treatment increased RhoA activity accompanied by the reduced tyrosine phosphorylation of SHP-2, which was reversed by LM11A-31. LM11A-31 also countered the effects of calpeptin, which activated RhoA by inhibiting SHP-2 tyrosine phosphatase. Therefore, suppression of RhoA signaling by LM11A-31 that blocks proNGF binding to p75(NTR) or activates SHP-2 tyrosine phosphatase downstream of NGF receptor enhances neuroprotection in experimental CIPN in mouse model.
    NeuroToxicology 09/2014; 45. DOI:10.1016/j.neuro.2014.09.005 · 3.38 Impact Factor
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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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    ABSTRACT: The p75 neurotrophin receptor (p75NTR) is involved in degenerative mechanisms related to Alzheimer's disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds.
    Journal of Alzheimer's disease: JAD 06/2014; 42(2). DOI:10.3233/JAD-140036 · 4.15 Impact Factor

  • The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2014; 34(5):2012-2012. DOI:10.1523/JNEUROSCI.0056-14.2014 · 6.34 Impact Factor
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    ABSTRACT: Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLCγ, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2013; 33(48):18712-18727. DOI:10.1523/JNEUROSCI.1310-13.2013 · 6.34 Impact Factor
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    Jian Shi · Frank M Longo · Stephen M Massa ·
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    ABSTRACT: The p75 neurotrophin receptor influences the proliferation, survival and differentiation of neuronal precursors and its expression is induced in injured brain, where it regulates cell survival. Here we test the hypotheses that pharmacologic modulation of p75(NTR) signaling will promote neural progenitor survival and proliferation, and improve outcomes of traumatic brain injury. LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75(NTR) signaling modulator, significantly increased proliferation and survival, and decreased JNK phosphorylation, in hippocampal neural stem/progenitor cells in culture expressing wildtype p75(NTR) , but had no effect on cells expressing a mutant neurotrophin-unresponsive form of the receptor. The compound also enhanced the production of mature neurons from adult hippocampal neural progenitors in vitro. In vivo, intranasal administration of LM11A-31 decreased post-injury hippocampal and cortical neuronal death, neural progenitor cell death, gliogenesis, and microglial activation, and enhanced long-term hippocampal neurogenesis and reversed spatial memory impairments. LM11A-31 diminished the post-injury increase of SOX2 expressing cells, but protected and increased the proliferation of endogenous PSA-NCAM positive progenitors, and restored the long-term production of mature granule neurons. These findings suggest that modulation of p75(NTR) actions using small molecules such as LM11A-31 may constitute a potent therapeutic strategy for traumatic brain injury. Stem Cells 2013.
    Stem Cells 11/2013; 31(11). DOI:10.1002/stem.1516 · 6.52 Impact Factor

  • Frank M Longo · Stephen M Massa ·
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    ABSTRACT: Neurotrophins and their receptors modulate multiple signalling pathways to regulate neuronal survival and to maintain axonal and dendritic networks and synaptic plasticity. Neurotrophins have potential for the treatment of neurological diseases. However, their therapeutic application has been limited owing to their poor plasma stability, restricted nervous system penetration and, importantly, the pleiotropic actions that derive from their concomitant binding to multiple receptors. One strategy to overcome these limitations is to target individual neurotrophin receptors — such as tropomyosin receptor kinase A (TRKA), TRKB, TRKC, the p75 neurotrophin receptor or sortilin — with small-molecule ligands. Such small molecules might also modulate various aspects of these signalling pathways in ways that are distinct from the programmes triggered by native neurotrophins. By departing from conventional neurotrophin signalling, these ligands might provide novel therapeutic options for a broad range of neurological indications.
    Nature Reviews Drug Discovery 07/2013; 12(7):507-25. DOI:10.1038/nrd4024 · 41.91 Impact Factor
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    ABSTRACT: BACKGROUND: . Effective recovery from functional impairments caused by traumatic brain injury (TBI) requires appropriate rehabilitation therapy. Multiple pathways are involved in secondary injury and recovery suggesting a role for multimodal approaches. OBJECTIVE: . Here, we examined the efficacy of the anti-inflammatory agent minocycline and botulinum toxin (botox)-induced limb constraint with structured physical therapy, delivered alone or in combination, after a severe TBI produced by a controlled cortical impact in rats. METHODS: . Minocycline was administered at 25 mg/kg daily for 2 weeks beginning 1 day after TBI or sham surgery. For constraint/physical therapy, botox-type A was injected into the nonaffected forearm muscle 1 day after injury and 2 weeks of physical therapy commenced at 5 days after injury. Functional evaluations were conducted 8 weeks after injury. RESULTS: . Minocycline, either as a monotherapy or as combination treatment with botox/physical therapy significantly reduced impairments of spatial learning and memory in the water maze test, whereas botox/physical therapy reduced forelimb motor asymmetry and improved manual dexterity in the cylinder and vermicelli handling tests, A synergistic effect between the 2 treatments was observed when rats performed tasks requiring dexterity. Inflammation was attenuated in the peri-contusion cortex and hippocampus in all TBI groups receiving mono or combination therapies, though there was no significant difference in lesion size among groups. CONCLUSION: . These data provide a rationale for incorporating anti-inflammatory treatment during rehabilitation therapy.
    Neurorehabilitation and neural repair 06/2013; 27(9). DOI:10.1177/1545968313491003 · 3.98 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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    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.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2013; 33(2):397-410. DOI:10.1523/JNEUROSCI.0399-12.2013 · 6.34 Impact Factor
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    ABSTRACT: Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B and p75 neurotrophin receptors. However, brain-derived neurotrophic factor is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets tropomyosin-related kinase B would promote neurogenesis and functional recovery after stroke. Four-month-old mice were trained on motor tasks before stroke. After stroke, functional test results were used to randomize mice into 2 equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for 10 weeks. LM22A-4 treatment significantly improved limb swing speed and accelerated the return to normal gait accuracy after stroke. LM22A-4 treatment also doubled both the number of new mature neurons and immature neurons adjacent to the stroke. Drug-induced differences were not observed in angiogenesis, dendritic arborization, axonal sprouting, glial scar formation, or neuroinflammation. A small molecule agonist of tropomyosin-related kinase B improves functional recovery from stroke and increases neurogenesis when administered beginning 3 days after stroke. These findings provide proof-of-concept that targeting of tropomyosin-related kinase B alone is capable of promoting one or more mechanisms relevant to stroke recovery. LM22A-4 or its derivatives might therefore serve as "pro-recovery" therapeutic agents for stroke.
    Stroke 04/2012; 43(7):1918-24. DOI:10.1161/STROKEAHA.111.641878 · 5.72 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) induces activation of microglia. Activated microglia can in turn increase secondary injury and impair recovery. This innate immune response requires hours to days to become fully manifest, thus providing a clinically relevant window of opportunity for therapeutic intervention. Microglial activation is regulated in part by poly(ADP-ribose) polymerase-1 (PARP-1). Inhibition of PARP-1 activity suppresses NF-kB-dependent gene transcription and thereby blocks several aspects of microglial activation. Here we evaluated the efficacy of a PARP inhibitor, INO-1001, in suppressing microglial activation after cortical impact in the rat. Rats were subjected to controlled cortical impact and subsequently treated with 10 mg/kg of INO-1001 (or vehicle alone) beginning 20 - 24 hours after the TBI. Brains were harvested at several time points for histological evaluation of inflammation and neuronal survival, using markers for microglial activation (morphology and CD11b expression), astrocyte activation (GFAP), and neuronal survival (NeuN). Rats were also evaluated at 8 weeks after TBI using measures of forelimb dexterity: the sticky tape test, cylinder test, and vermicelli test. Peak microglial and astrocyte activation was observed 5 to 7 days after this injury. INO-1001 significantly reduced microglial activation in the peri-lesion cortex and ipsilateral hippocampus. No rebound inflammation was observed in rats that were treated with INO-1001 or vehicle for 12 days followed by 4 days without drug. The reduced inflammation was associated with increased neuronal survival in the peri-lesion cortex and improved performance on tests of forelimb dexterity conducted 8 weeks after TBI. Treatment with a PARP inhibitor for 12 days after TBI, with the first dose given as long as 20 hours after injury, can reduce inflammation and improve histological and functional outcomes.
    Journal of Neuroinflammation 02/2012; 9(1):31. DOI:10.1186/1742-2094-9-31 · 5.41 Impact Factor
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    ABSTRACT: Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2012; 32(5):1803-10. DOI:10.1523/JNEUROSCI.0865-11.2012 · 6.34 Impact Factor
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    ABSTRACT: Background: There is evidence that interaction with biologically important metals, particularly copper and iron, contributes to the pathological aggregation and toxicity of the mutant huntingtin protein in HD. PBT2 is a novel 8-hydroxyquinoline drug in clinical trials for AD and HD which restores metal homeostasis and has demonstrated neuroprotective and cognitive benefits in animal models of AD and in a Phase IIa clinical trial in AD patients. Objectives: We assessed efficacy of PBT2 to improve function in nematode and mouse models of HD. Methods: We assessed the effects of PBT2 on motility in a strain of C. elegans engineered to overexpress an extended polyglutamine tract. We then assessed the effects of daily oral administration of PBT2 on the R6/2 mouse a vertebrate model of HD. Behavioural measures (Rotarod performance, clasping latency and duration) and measures of overall health (body weight, lifespan) were assessed throughout the study. At conclusion brains were evaluated for weight and lateral ventricle area. Results: PBT2 significantly decreased paralysis caused by overexpression of an extended polyglutamine tract in a C. elegans. R6/2 mice treated with PBT2 showed significantly better performance in the Rotarod task and significantly decreased duration of clasping than control animals. Mean body weight and brain weight in the PBT2 treatment group were significantly higher than the control cohort and median lifespan was prolonged by 26%. Mean lateral ventricle area in the PBT2-treated group was 46% smaller than in the control group. Conclusions: Treatment with PBT2 may be beneficial as a disease modifying therapy for HD.
    Journal of Huntington's disease 01/2012; 1(2):(In Press 17 Nov 2012). DOI:10.3233/JHD-120029

  • Alzheimer's and Dementia 07/2011; 7(4). DOI:10.1016/j.jalz.2011.05.1323 · 12.41 Impact Factor
  • Jian Shi · Dongmin Wang · Tina I. Lam · Raymond A. Swanson · Stephen M. Massa ·

    International Stroke Conference; 03/2011
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) activates the receptor tropomyosin-related kinase B (TrkB) with high potency and specificity, promoting neuronal survival, differentiation, and synaptic function. Correlations between altered BDNF expression and/or function and mechanism(s) underlying numerous neurodegenerative conditions, including Alzheimer disease and traumatic brain injury, suggest that TrkB agonists might have therapeutic potential. Using in silico screening with a BDNF loop-domain pharmacophore, followed by low-throughput in vitro screening in mouse fetal hippocampal neurons, we have efficiently identified small molecules with nanomolar neurotrophic activity specific to TrkB versus other Trk family members. Neurotrophic activity was dependent on TrkB and its downstream targets, although compound-induced signaling activation kinetics differed from those triggered by BDNF. A selected prototype compound demonstrated binding specificity to the extracellular domain of TrkB. In in vitro models of neurodegenerative disease, it prevented neuronal degeneration with efficacy equal to that of BDNF, and when administered in vivo, it caused hippocampal and striatal TrkB activation in mice and improved motor learning after traumatic brain injury in rats. These studies demonstrate the utility of loop modeling in drug discovery and reveal what we believe to be the first reported small molecules derived from a targeted BDNF domain that specifically activate TrkB.We propose that these compounds constitute a novel group of tools for the study of TrkB signaling and may provide leads for developing new therapeutic agents for neurodegenerative diseases.
    The Journal of clinical investigation 05/2010; 120(5):1774-85. DOI:10.1172/JCI41356 · 13.22 Impact Factor
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    ABSTRACT: Oligomeric forms of amyloid-beta (Abeta) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75(NTR)) has been implicated in Abeta-induced neurodegeneration. To further define the functions of p75(NTR) in AD, we examined the interaction of oligomeric Abeta(1-42) with p75(NTR), and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Abeta, and fluorescence resonance energy transfer analysis revealed that Abeta oligomers interact with the extracellular domain of p75(NTR). In vitro studies of Abeta-induced death in neuron cultures isolated from wild-type and p75(NTR-/-) mice, in which the p75(NTR) extracellular domain is deleted, showed reduced sensitivity of mutant cells to Abeta-induced cell death. Interestingly, Abeta-induced neuritic dystrophy and activation of c-Jun, a known mediator of Abeta-induced deleterious signaling, were completely prevented in p75(NTR-/-) neuron cultures. Thy1-hAPP(Lond/Swe) x p75(NTR-/-) mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75(NTR). Abeta levels were not affected, suggesting that removal of p75(NTR) extracellular domain reduced the ability of excess Abeta to promote neuritic degeneration. These findings indicate that although p75(NTR) likely does not mediate all Abeta effects, it does play a significant role in enabling Abeta-induced neurodegeneration in vitro and in vivo, establishing p75(NTR) as an important therapeutic target for AD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2009; 29(34):10627-37. DOI:10.1523/JNEUROSCI.0620-09.2009 · 6.34 Impact Factor

Publication Stats

3k Citations
324.51 Total Impact Points


  • 1992-2015
    • University of California, San Francisco
      • • Department of Neurology
      • • Veterans Affairs Medical Center
      • • Department of Psychiatry
      San Francisco, California, United States
  • 2013
    • Stanford University
      • Department of Neurology and Neurological Sciences
      Palo Alto, CA, United States
  • 2003-2010
    • University of North Carolina at Chapel Hill
      • Department of Neurology
      North Carolina, United States
  • 1994-2007
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2006
    • CSU Mentor
      • Department of Neurology
      Long Beach, California, United States