Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
| Autor: | Johan Sandin, Erika Vázquez-Juárez, Magnus M. Halldin, Gunnar Nordvall, Märta Dahlström, Maria Lindskog, Maria Eriksdotter, Pontus Forsell, Bengt Winblad, Nather Madjid |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male cognition Tropomyosin receptor kinase B Tropomyosin receptor kinase A Rats Sprague-Dawley 0302 clinical medicine Biology (General) Nootropic Agents Membrane Glycoproteins Behavior Animal Triazines TrkA Neurodegeneration Age Factors TrkB Brain Long-term potentiation General Medicine Protein-Tyrosine Kinases brain derived neurotrophic factor Alzheimer’s disease Neurotrophin Signal Transduction QH301-705.5 Receptors Nerve Growth Factor Biology Motor Activity Article nerve growth factor Small Molecule Libraries 03 medical and health sciences Cell Line Tumor medicine Animals Humans Receptor trkB Cognitive Dysfunction Receptor trkA Maze Learning Brain-derived neurotrophic factor medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Nerve growth factor nervous system Trk receptor biology.protein Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Cells Volume 10 Issue 8 Cells, Vol 10, Iss 1871, p 1871 (2021) |
| ISSN: | 2073-4409 |
| Popis: | Alzheimer’s disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. Our aim was to identify small molecules with stimulatory effects on the signaling of two neurotrophins, the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF). To identify molecules that could potentiate neurotrophin signaling, 25,000 molecules were screened, which led to the identification of the triazinetrione derivatives ACD855 (Ponazuril) and later on ACD856, as positive allosteric modulators of tropomyosin related kinase (Trk) receptors. ACD855 or ACD856 potentiated the cellular signaling of the neurotrophin receptors with EC50 values of 1.9 and 3.2 or 0.38 and 0.30 µM, respectively, for TrkA or TrkB. ACD855 increased acetylcholine levels in the hippocampus by 40% and facilitated long term potentiation in rat brain slices. The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models. Finally, the age-induced cognitive dysfunction in 18-month-old mice could be restored to the same level as found in 2-month-old mice after a single treatment of ACD856. We have identified a novel mechanism to modulate the activity of the Trk-receptors. The identification of the positive allosteric modulators of the Trk-receptors might have implications for the treatment of Alzheimer’s diseases and other diseases characterized by cognitive impairment. |
| Databáze: | OpenAIRE |
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