ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

Canelif Yilmaz; Thanasis Rogdakis; Alessia Latorrata; Evangelia Thanou; Eleftheria Karadima; Eleni Papadimitriou; Eleni Siapi; Ka Wan Li; Theodora Katsila; Theodora Calogeropoulou; Ioannis Charalampopoulos; Vasileia Ismini Alexaki

doi:10.3390/biom12030424

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

Canelif Yilmaz, Thanasis Rogdakis, Alessia Latorrata, Evangelia Thanou, Eleftheria Karadima, Eleni Papadimitriou, Eleni Siapi, Ka Wan Li, Theodora Katsila, Theodora Calogeropoulou, Ioannis Charalampopoulos, Vasileia Ismini Alexaki^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Tackling neurodegeneration and neuroinflammation is particularly challenging due to the complexity of central nervous system (CNS) disorders, as well as the limited drug accessibility to the brain. The activation of tropomyosin-related kinase A (TRKA) receptor signaling by the nerve growth factor (NGF) or the neurosteroid dehydroepiandrosterone (DHEA) may combat neurodegeneration and regulate microglial function. In the present study, we synthesized a C-17-spiro-cyclopropyl DHEA derivative (ENT-A010), which was capable of activating TRKA. ENT-A010 protected PC12 cells against serum starvation-induced cell death, dorsal root ganglia (DRG) neurons against NGF deprivation-induced apoptosis and hippocampal neurons against Aβ-induced apoptosis. In addition, ENT-A010 pretreatment partially restored homeostatic features of microglia in the hippocampus of lipopolysaccharide (LPS)-treated mice, enhanced Aβ phagocytosis, and increased Ngf expression in microglia in vitro. In conclusion, the small molecule ENT-A010 elicited neuroprotective effects and modulated microglial function, thereby emerging as an interesting compound, which merits further study in the treatment of CNS disorders.

Original language	English
Article number	424
Pages (from-to)	1-22
Number of pages	22
Journal	Biomolecules
Volume	12
Issue number	3
Early online date	12 Mar 2022
DOIs	https://doi.org/10.3390/biom12030424
Publication status	Published - Mar 2022

Bibliographical note

Special Issue: Molecular and Cellular Mechanisms of Neuroinflammation.

Funding Information:
Funding: This work was supported by grants from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No 765704 to V.I.A., G.H., T.C. and K.W.L.) and the Deutsche Forschungsgemeinschaft (SFB/TRR 205 to V.I.A.).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Aβ
DHEA
ENT-A010
Hippocampus
Microglia
Neuroprotection
Phagocytosis
TRKA

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/biom12030424

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Yilmaz, C., Rogdakis, T., Latorrata, A., Thanou, E., Karadima, E., Papadimitriou, E., Siapi, E., Li, K. W., Katsila, T., Calogeropoulou, T., Charalampopoulos, I., & Alexaki, V. I. (2022). ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses. Biomolecules, 12(3), 1-22. Article 424. https://doi.org/10.3390/biom12030424

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title = "ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses",

abstract = "Tackling neurodegeneration and neuroinflammation is particularly challenging due to the complexity of central nervous system (CNS) disorders, as well as the limited drug accessibility to the brain. The activation of tropomyosin-related kinase A (TRKA) receptor signaling by the nerve growth factor (NGF) or the neurosteroid dehydroepiandrosterone (DHEA) may combat neurodegeneration and regulate microglial function. In the present study, we synthesized a C-17-spiro-cyclopropyl DHEA derivative (ENT-A010), which was capable of activating TRKA. ENT-A010 protected PC12 cells against serum starvation-induced cell death, dorsal root ganglia (DRG) neurons against NGF deprivation-induced apoptosis and hippocampal neurons against Aβ-induced apoptosis. In addition, ENT-A010 pretreatment partially restored homeostatic features of microglia in the hippocampus of lipopolysaccharide (LPS)-treated mice, enhanced Aβ phagocytosis, and increased Ngf expression in microglia in vitro. In conclusion, the small molecule ENT-A010 elicited neuroprotective effects and modulated microglial function, thereby emerging as an interesting compound, which merits further study in the treatment of CNS disorders.",

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author = "Canelif Yilmaz and Thanasis Rogdakis and Alessia Latorrata and Evangelia Thanou and Eleftheria Karadima and Eleni Papadimitriou and Eleni Siapi and Li, {Ka Wan} and Theodora Katsila and Theodora Calogeropoulou and Ioannis Charalampopoulos and Alexaki, {Vasileia Ismini}",

note = "Special Issue: Molecular and Cellular Mechanisms of Neuroinflammation. Funding Information: Funding: This work was supported by grants from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement (No 765704 to V.I.A., G.H., T.C. and K.W.L.) and the Deutsche Forschungsgemeinschaft (SFB/TRR 205 to V.I.A.). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

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language = "English",

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AU - Yilmaz, Canelif

AU - Rogdakis, Thanasis

AU - Latorrata, Alessia

AU - Thanou, Evangelia

AU - Karadima, Eleftheria

AU - Papadimitriou, Eleni

AU - Siapi, Eleni

AU - Li, Ka Wan

AU - Katsila, Theodora

AU - Calogeropoulou, Theodora

AU - Charalampopoulos, Ioannis

AU - Alexaki, Vasileia Ismini

N1 - Special Issue: Molecular and Cellular Mechanisms of Neuroinflammation. Funding Information: Funding: This work was supported by grants from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No 765704 to V.I.A., G.H., T.C. and K.W.L.) and the Deutsche Forschungsgemeinschaft (SFB/TRR 205 to V.I.A.). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/3

Y1 - 2022/3

N2 - Tackling neurodegeneration and neuroinflammation is particularly challenging due to the complexity of central nervous system (CNS) disorders, as well as the limited drug accessibility to the brain. The activation of tropomyosin-related kinase A (TRKA) receptor signaling by the nerve growth factor (NGF) or the neurosteroid dehydroepiandrosterone (DHEA) may combat neurodegeneration and regulate microglial function. In the present study, we synthesized a C-17-spiro-cyclopropyl DHEA derivative (ENT-A010), which was capable of activating TRKA. ENT-A010 protected PC12 cells against serum starvation-induced cell death, dorsal root ganglia (DRG) neurons against NGF deprivation-induced apoptosis and hippocampal neurons against Aβ-induced apoptosis. In addition, ENT-A010 pretreatment partially restored homeostatic features of microglia in the hippocampus of lipopolysaccharide (LPS)-treated mice, enhanced Aβ phagocytosis, and increased Ngf expression in microglia in vitro. In conclusion, the small molecule ENT-A010 elicited neuroprotective effects and modulated microglial function, thereby emerging as an interesting compound, which merits further study in the treatment of CNS disorders.

AB - Tackling neurodegeneration and neuroinflammation is particularly challenging due to the complexity of central nervous system (CNS) disorders, as well as the limited drug accessibility to the brain. The activation of tropomyosin-related kinase A (TRKA) receptor signaling by the nerve growth factor (NGF) or the neurosteroid dehydroepiandrosterone (DHEA) may combat neurodegeneration and regulate microglial function. In the present study, we synthesized a C-17-spiro-cyclopropyl DHEA derivative (ENT-A010), which was capable of activating TRKA. ENT-A010 protected PC12 cells against serum starvation-induced cell death, dorsal root ganglia (DRG) neurons against NGF deprivation-induced apoptosis and hippocampal neurons against Aβ-induced apoptosis. In addition, ENT-A010 pretreatment partially restored homeostatic features of microglia in the hippocampus of lipopolysaccharide (LPS)-treated mice, enhanced Aβ phagocytosis, and increased Ngf expression in microglia in vitro. In conclusion, the small molecule ENT-A010 elicited neuroprotective effects and modulated microglial function, thereby emerging as an interesting compound, which merits further study in the treatment of CNS disorders.

KW - Aβ

KW - DHEA

KW - ENT-A010

KW - Hippocampus

KW - Microglia

KW - Neuroprotection

KW - Phagocytosis

KW - TRKA

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SN - 2218-273X

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EP - 22

JO - Biomolecules

JF - Biomolecules

IS - 3

M1 - 424

ER -

ENT-A010, a Novel Steroid Derivative, Displays Neuroprotective Functions and Modulates Microglial Responses

Abstract

Bibliographical note

Keywords

UN SDGs

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