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- W1977796667 abstract "The activation of the TrkB receptor tyrosine kinase by Brain-Derived Neurotrophic Factor (BDNF) regulates neuronal plasticity and survival, and virally-mediated BDNF expression and exogenous BDNF protein delivery promote synaptic integrity and improve behavior in models of aging and Alzheimer's disease (AD). In prior work, since the pharmacokinetic profile of BDNF protein is not conducive to drug development, we undertook identification of small molecule activators of TrkB signaling. Using BDNF loop 2 as a model for virtual compound library screening and following with cell-based screening, we found a group of chemically diverse compounds (LM22A1-4) that: promoted hippocampal neuron survival with nanomolar potency; activated TrkB, but not TrkA or C; and, upregulated ERK and AKT activation in vitro. LM22A-4 was further shown to: bind to TrkB; activate in vivo hippocampal and striatal TrkB, ERK and AKT and improve motor learning following traumatic brain injury when given intranasally (IN). In addition, the compound inhibited death of hippocampal neurons in culture exposed to Aß oligomers. To continue to search for compounds with enhanced pharmacologic properties, LM22A structures were used as models to search an ∼10 million compound library for compounds of similar pharmacophoric structure. Screening in primary hippocampal cultures revealed another group of survival-promoting compounds with similar effects on TrkB-related signaling. The effects of one of these second generation compounds (BD2-A) on pathology and learning deficits have been evaluated in a mouse AD model. BD2-A (administered intraperitoneally and IN) restored neurite length and spine density in the hippocampi of APP (London/Swedish) mutant mice, and significantly improved their performance in the Y maze task. Small BDNF-mimetic compounds may have effects similar to BDNF in vivo, biasing signaling toward cell survival, and maintenance of neuritic structure and plasticity. These results suggest that these compounds or their derivatives may be useful in the treatment of Alzheimer's and other neurodegenerative diseases." @default.
- W1977796667 created "2016-06-24" @default.
- W1977796667 creator A5077249061 @default.
- W1977796667 date "2011-07-01" @default.
- W1977796667 modified "2023-10-16" @default.
- W1977796667 title "S3-02-06: Small molecule BDNF mimetics" @default.
- W1977796667 doi "https://doi.org/10.1016/j.jalz.2011.05.2368" @default.
- W1977796667 hasPublicationYear "2011" @default.
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