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

Cells

Johan Sandin¹  Nather Madjid¹  Märta Dahlström¹  Gunnar Nordvall¹  Magnus M. Halldin¹  Pontus Forsell¹  Maria Eriksdotter²  Erika Vazquez-Juarez³  Maria Lindskog³  Bengt Winblad³ 

[1] AlzeCure Pharma AB, 141 57 Huddinge, Sweden;Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 141 83 Huddinge, Sweden;Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77 Solna, Sweden;

关键词: brain derived neurotrophic factor;    nerve growth factor;    TrkA;    TrkB;    cognition;    Alzheimer’s disease;   

DOI  :  10.3390/cells10081871

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown