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
Affiliations
Canelif Yilmaz
Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Thanasis Rogdakis
Pharmacology Department, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
Alessia Latorrata
Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
Evangelia Thanou
Center for Neurogenomics and Cognitive Research, Department of Molecular and Cellular Neurobiology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
Eleftheria Karadima
Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Eleni Papadimitriou
Pharmacology Department, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
Eleni Siapi
Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
Ka Wan Li
Center for Neurogenomics and Cognitive Research, Department of Molecular and Cellular Neurobiology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
Theodora Katsila
Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
Theodora Calogeropoulou
Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece
Ioannis Charalampopoulos
Pharmacology Department, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
Vasileia Ismini Alexaki
Institute of Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
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.
