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Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction

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 hippo...

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Autores principales: Dahlström, Märta, Madjid, Nather, Nordvall, Gunnar, Halldin, Magnus M., Vazquez-Juarez, Erika, Lindskog, Maria, Sandin, Johan, Winblad, Bengt, Eriksdotter, Maria, Forsell, Pontus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391421/
https://www.ncbi.nlm.nih.gov/pubmed/34440640
http://dx.doi.org/10.3390/cells10081871
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author Dahlström, Märta
Madjid, Nather
Nordvall, Gunnar
Halldin, Magnus M.
Vazquez-Juarez, Erika
Lindskog, Maria
Sandin, Johan
Winblad, Bengt
Eriksdotter, Maria
Forsell, Pontus
author_facet Dahlström, Märta
Madjid, Nather
Nordvall, Gunnar
Halldin, Magnus M.
Vazquez-Juarez, Erika
Lindskog, Maria
Sandin, Johan
Winblad, Bengt
Eriksdotter, Maria
Forsell, Pontus
author_sort Dahlström, Märta
collection PubMed
description 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 EC(50) 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.
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spelling pubmed-83914212021-08-28 Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction Dahlström, Märta Madjid, Nather Nordvall, Gunnar Halldin, Magnus M. Vazquez-Juarez, Erika Lindskog, Maria Sandin, Johan Winblad, Bengt Eriksdotter, Maria Forsell, Pontus Cells Article 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 EC(50) 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. MDPI 2021-07-23 /pmc/articles/PMC8391421/ /pubmed/34440640 http://dx.doi.org/10.3390/cells10081871 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dahlström, Märta
Madjid, Nather
Nordvall, Gunnar
Halldin, Magnus M.
Vazquez-Juarez, Erika
Lindskog, Maria
Sandin, Johan
Winblad, Bengt
Eriksdotter, Maria
Forsell, Pontus
Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
title Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
title_full Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
title_fullStr Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
title_full_unstemmed Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
title_short Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
title_sort identification of novel positive allosteric modulators of neurotrophin receptors for the treatment of cognitive dysfunction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391421/
https://www.ncbi.nlm.nih.gov/pubmed/34440640
http://dx.doi.org/10.3390/cells10081871
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