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

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

doi:10.3390/biom12030424

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.

Highlights

We and others have shown that nerve growth factor (NGF) can exert anti-inflammatory effects and promote Aβ clearance in microglia [42,43]
We have demonstrated that steroid molecules can share similar functions with neurotrophins in terms of neuroprotection and anti-inflammatory effects and could be, interesting candidates for the treatment of central nervous system (CNS) disorders involving neurodegeneration and neuroinflammation [11,25–30,38–41,80–83]
The neurosteroid DHEA was shown to bind to tropomyosin-related kinase A (TRKA) receptor and activate downstream signaling in neuronal cells and microglia, thereby promoting neuronal survival and dampening microglia-mediated neuroinflammation [26,28,38]

Summary

Introduction

Neurodegeneration and neuroinflammation are fundamental hallmarks of central nervous system (CNS) disorders [1]. Neurodegeneration refers to the impaired function and loss of neurons, which is often permanent due to the limited regenerative capacity of the adult neural system [2]. Neuroinflammation involves the inflammatory activation of glial cells, that is, microglia and astrocytes, and can have protective or destructive consequences for the neural system [1,3]. Microglia play a key role in the maintenance of homeostasis due to synaptic pruning and their clearing and neurotrophic function [3–5], while their inflammatory activation is a prerequisite for elimination of insults

Methods

Results

Conclusion