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.
View: Text | PDF
Technical Advance Neuroscience Article has an altmetric score of 14

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

×

Figure 2

Neurotrophic activities of LM22A compounds.

Options: View larger image (or click on image) Download as PowerPoint
Neurotrophic activities of LM22A compounds. (A) Fluorescence photomicrog...
(A) Fluorescence photomicrographs (original magnification, ×40) of GAP43-immunostained E16 mouse hippocampal neuronal cultures treated with culture medium (CM), BDNF, or LM22A-4 (#4) for 48 hours. (B–E) Neuron survival dose-response curves for BDNF and LM22A compounds. Counts were normalized to survival achieved with 20 ng/ml (~0.7 nM) BDNF. For BDNF, survival values for each concentration were derived from n = 29–32 wells obtained from 12 separate experiments; for LM22A-1, -2, and -3, values for each concentration were derived from n = 11–19 wells obtained from 6 separate experiments; for LM22A-4, values for each concentration were derived from n = 13–21 wells obtained from 8 separate experiments. White circles, compound responses; black circles, BDNF responses (F) Comparison of survival curves from all compounds and BDNF. (G) Quantitation of the fraction of TUNEL-positive/DAPI-staining cells demonstrates that LM22A compounds decrease the number of TUNEL-positive cells to a degree similar to that of BDNF. A total of n = 93–95 fields per condition derived from 3 separate assays were counted. (H) Survival analysis of E16 hippocampal neurons treated with nonimmune serum (Control) or antibody to BDNF (Ab; 1:400) and BDNF (0.7 nM) or LM22A compounds (500 nM). Counts made in a total of n = 10–12 wells were derived from 5–6 experiments. (I) Survival of E16 hippocampal neurons treated with BDNF alone (0.7 nM), LM22A-4 alone (500 nM), or BDNF plus LM22A-4. n = 24–72 wells for each condition derived from 3 experiments were analyzed. *P < 0.05, **P < 0.01, ***P < 0.001.