Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Neurotrophin Analog ENT-A044 Activates the p75 Neurotrophin Receptor Promoting Cell Death in Mouse and Human Neuronal Cells

M. A. Papadopoulou
ORCID logo ,
T. Rogdakis
ORCID logo ,
D. Charou
,
M. Peteinareli
,
K. Ntarntani
,
A. Gravanis
ORCID logo ,
K. Chanoumidou
,
I. Charalampopoulos
* ORCID logo
Version 1 : Received: 21 June 2023 / Approved: 22 June 2023 / Online: 22 June 2023 (13:00:08 CEST)

A peer-reviewed article of this Preprint also exists.

Papadopoulou, M.A.; Rogdakis, T.; Charou, D.; Peteinareli, M.; Ntarntani, K.; Gravanis, A.; Chanoumidou, K.; Charalampopoulos, I. Neurotrophin Analog ENT-A044 Activates the p75 Neurotrophin Receptor, Regulating Neuronal Survival in a Cell Context-Dependent Manner. Int. J. Mol. Sci. 2023, 24, 11683. Papadopoulou, M.A.; Rogdakis, T.; Charou, D.; Peteinareli, M.; Ntarntani, K.; Gravanis, A.; Chanoumidou, K.; Charalampopoulos, I. Neurotrophin Analog ENT-A044 Activates the p75 Neurotrophin Receptor, Regulating Neuronal Survival in a Cell Context-Dependent Manner. Int. J. Mol. Sci. 2023, 24, 11683.

Abstract

Neuronal cell fate is predominantly controlled by the effects of growth factors, such as neurotrophins, and the activation of a variety of signaling pathways acting through neurotrophin receptors, namely Trk and p75 (p75NTR). Despite their beneficial effects on brain function, their therapeutic use is compromised, due to their polypeptidic nature and blood–brain-barrier impermeability. To overcome these limitations, our previous studies have proven that DHEA-derived synthetic analogs can act like neurotrophins, lacking endocrine side effects. The present study focuses on the biological characterization of a newly synthesized analog, ENT-A044, and its role on inducing cell specific functions of p75NTR. We show that ENT-A044 can induce cell death and phosphorylation of JNK protein by activating p75NTR. Additionally, ENT-A044 can induce the phosphorylation of TrkB receptor, indicating that our molecule can activate both neurotrophin receptors, leading towards the protection of neuronal populations that express both receptors. Furthermore, the present study demonstrates for the first time the expression of p75NTR in human induced Pluripotent Stem Cells - derived Neural Progenitor Cells (hiPSCs - derived NPCs) and receptor-dependent cell death induced by ENT-A044 treatment. In conclusion, ENT-A044 could be proven a lead molecule for the development of novel pharmacological agents, aiming on new therapeutic approaches and research tools, by controlling p75NTR actions.

Keywords

neurotrophins; p75 receptor; steroidal synthetic analogs; TrkB receptor; cell death; neural stem cells; human induced pluripotent stem cells

Subject

Medicine and Pharmacology, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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