ArticleThe Journal of clinical investigation2010
Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents.
Article in The Journal of clinical investigation, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 197 papers.
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Who cites it
197 citing papers in PubMed, 415 citations in OpenAlex.
- Targeting receptor tyrosine kinases: from molecular mechanisms to clinical therapeutics.Signal transduction and targeted therapy · 2026Review
- A De Novo Peptide That Induces Axonal Growth Through TrkB Activation.Chembiochem : a European journal of chemical biology · 2026Article
- Protective Effects of Pomiferin on Aluminum Chloride-induced Memory Impairment: Evidence from Behavioral, Biochemical, and Insilico Studies.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2026Article
- A novel synthetic 3,4,5-tri-feruloylquinic acid enhances learning and memory via neurotrophin signaling in an aging model senescence-accelerated prone 8 mice.GeroScience · 2026Article
- Amyloid β Instigates Cardiac Neurotrophic Signaling Impairment, Driving Alzheimer's Associated Heart Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- BDNF in ventrolateral orbitofrontal cortex to dorsolateral striatum circuit moderates alcohol consumption, seeking and relapse.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Integrating neuroprotection, antioxidative effects, and precision medicine in glaucoma management with bioactive compounds.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Review
- The Heart-Brain Axis in the Artificial Intelligence Era: Integrating Old and New Insights Towards New Targeting and Innovative Neuro- and Cardio-Therapeutics.International journal of molecular sciences · 2025Review
- Acceleration-Dependent Effects of Vibrotactile Gamma Stimulation on Cognitive Recovery and Cholinergic Function in a Scopolamine-Induced Neurotoxicity Mouse Model.Biomedicines · 2025Article
- Small-Molecule Trk Agonists: Where Do We Go from Here?Journal of medicinal chemistry · 2025Review
- MeCP2 prevents against sustained ketamine-induced synaptic depression at inhibitory synapses.iScience · 2025Article
- CXCL12 Engages Cortical Inhibitory Neurons to Enhance Dendritic Spine Plasticity and Structured Network Activity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Unlocking Alzheimer's Disease: The Role of BDNF Signaling in Neuropathology and Treatment.Neuromolecular medicine · 2025Review
- The Role of Brain-Derived Neurotrophic Factor as an Essential Mediator in Neuronal Functions and the Therapeutic Potential of Its Mimetics for Neuroprotection in Neurologic and Psychiatric Disorders.Molecules (Basel, Switzerland) · 2025Review
- A Small-Molecule TrkB/TrkC Ligand Promotes Neurogenesis and Behavioral Recovery Following Traumatic Brain Injury.Neurotrauma reports · 2025Article
- Long-term functional rescue of trauma-induced vision loss by a novel, small molecule TrkB modulator.PloS one · 2025Article
- Selective, Intrinsically Fluorescent Trk Modulating Probes.ACS chemical neuroscience · 2024Article
- Tremendous Fidelity of Vitamin D3 in Age-related Neurological Disorders.Molecular neurobiology · 2024Review
- A Combined Computational and Experimental Approach to Studying Tropomyosin Kinase Receptor B Binders for Potential Treatment of Neurodegenerative Diseases.Molecules (Basel, Switzerland) · 2024Article
- Neurotrophins and Their Receptors: BDNF's Role in GABAergic Neurodevelopment and Disease.International journal of molecular sciences · 2024Review
137 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.