Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents
Stephen M. Massa, … , Jayakumar Rajadas, Frank M. Longo
Stephen M. Massa, … , Jayakumar Rajadas, Frank M. Longo
Published April 19, 2010
Citation Information: J Clin Invest. 2010;120(5):1774-1785. https://doi.org/10.1172/JCI41356.
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Technical Advance Neuroscience

Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents

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.

Authors

Stephen M. Massa, Tao Yang, Youmei Xie, Jian Shi, Mehmet Bilgen, Jeffrey N. Joyce, Dean Nehama, Jayakumar Rajadas, Frank M. Longo

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Figure 7

LM22A-4 inhibits neuronal death in in vitro neurodegenerative disease models.

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LM22A-4 inhibits neuronal death in in vitro neurodegenerative disease mo...
(A) Six- to 7-DIV hippocampal neurons from E16 mice were treated in the absence of Aβ with CM alone or CM + K252a (K) or in the presence of oligomeric Aβ with CM alone, CM + K252a, BDNF (0.7 nM), BDNF + K252a, LM22A-4 (500 nM), LM22A-4 + K252a. K252a was used at 200 nM. After 72 hours, cultures were assessed by TUNEL/DAPI staining. n = 28–29 fields for each condition derived from a total of 3 experiments. (B) SH-SY5Y human neuroblastoma cells were pretreated for 3 days in the following conditions: CM alone, CM + K252a, BDNF (0.7 nM), BDNF + K252a, LM22A-4 (500 nM), LM22A-4 + K252a. MPP+ (100 μM) was added, and 48 hours later cell survival was assessed by MTT/cell count assay. (C) Six- to 7-DIV striatal neurons from E16 mice were pretreated for 2 hours in the following conditions: CM, CM + K252a, BDNF (0.7 nM), BDNF + K252a, LM22A-4 (500 nM), LM22A-4 + K252a. QA (7.5 mM) was added, and after 24 hours numbers of DARPP-32–positive/total surviving cells was determined. n = 50–100 fields for each condition derived from a total 5 experiments. *P < 0.05, **P < 0.01, ***P < 0.001.