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3?, 6?-dichloro-5-hydroxy-5?-cholestane facilitates neuronal development through modulating TrkA signaling regulated proteins in primary hippocampal neuron.

ABSTRACT: Potentiating neuritogenesis through pharmacological intervention might hold therapeutic promise in neurodegenerative disorders and acute brain injury. Here, we investigated the novel neuritogenic potentials of a steroidal chlorohydrin, 3?, 6?-dichloro-5-hydroxy-5?-cholestane (hereafter, SCH) and the change in cellular proteome to gain insight into the underlying mechanism of its neurotrophic activity in hippocampal neurons. Morphometric analysis showed that SCH promoted early neuronal differentiation, dendritic arborization and axonal maturation. Proteomic and bioinformatic analysis revealed that SCH induced upregulation of several proteins, including those associated with neuronal differentiation and development. Immunocytochemical data further indicates that SCH-treated neurons showed upregulation of Hnrnpa2b1 and Map1b, validating their proteomic profiles. In addition, a protein-protein interaction network analysis identified TrkA as a potential target connecting most of the upregulated proteins. The neurite outgrowth effect of SCH was suppressed by TrkA inhibitor, GW441756, verifying TrkA-dependent activity of SCH, which further supports the connection of TrkA with the upregulated proteins. Also, the computational analysis revealed that SCH interacts with the NGF-binding domain of TrkA through Phe327 and Asn355. Collectively, our findings provide evidence that SCH promotes neuronal development via upregulating TrkA-signaling proteins and suggest that SCH could be a promising therapeutic agent in the prevention and treatment of neurodegenerative disorders.

SUBMITTER: Hannan MA

PROVIDER: S-EPMC6908615 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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3β, 6β-dichloro-5-hydroxy-5α-cholestane facilitates neuronal development through modulating TrkA signaling regulated proteins in primary hippocampal neuron.

Hannan Md Abdul MA Haque Md Nazmul MN Dash Raju R Alam Mahboob M Moon Il Soo IS

Scientific reports 20191212 1

Potentiating neuritogenesis through pharmacological intervention might hold therapeutic promise in neurodegenerative disorders and acute brain injury. Here, we investigated the novel neuritogenic potentials of a steroidal chlorohydrin, 3β, 6β-dichloro-5-hydroxy-5α-cholestane (hereafter, SCH) and the change in cellular proteome to gain insight into the underlying mechanism of its neurotrophic activity in hippocampal neurons. Morphometric analysis showed that SCH promoted early neuronal differenti ...[more]

PMID: 31831796

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Project description:The present study describes the synthesis, characterization, and in vitro molecular interactions of a steroid 3β,6β-diacetoxy-5α-cholestan-5-ol. Through conventional and solid-state methods, a cholestane derivative was successfully synthesized, and a variety of analytical techniques were employed to confirm its identity, including high-resolution mass spectrometry (HRMS), Fourier transforms infrared (FT-IR), nuclear magnetic resonance (NMR), elemental analysis, and X-ray single-crystal diffraction. Optimizing the geometry of the steroid was undertaken using density functional theory (DFT), and the results showed great concordance with the data from the experiments. Fluorescence spectral methods and ultraviolet-vis absorption titration were employed to study the in vitro molecular interaction of the steroid regarding human serum albumin (HSA). The Stern-Volmer, modified Stern-Volmer, and thermodynamic parameters' findings showed that steroids had a significant binding affinity to HSA and were further investigated by molecular docking studies to understand the participation of active amino acids in forming non-bonding interactions with steroids. Fluorescence studies have shown that compound 3 interacts with human serum albumin (HSA) through a static quenching mechanism. The binding affinity of compound 3 for HSA was found to be 3.18 × 104 mol-1, and the Gibbs free energy change (ΔG) for the binding reaction was -9.86 kcal mol-1 at 298 K. This indicates that the binding of compound 3 to HSA is thermodynamically favorable. The thermodynamic parameters as well as the binding score obtained from molecular docking at various Sudlow's sites was -8.2, -8.5, and -8.6 kcal/mol for Sites I, II, and III, respectively, supporting the system's spontaneity. Aside from its structural properties, the steroid demonstrated noteworthy antioxidant activity, as evidenced by its IC50 value of 58.5 μM, which is comparable to that of ascorbic acid. The findings presented here contribute to a better understanding of the pharmacodynamics of steroids.

Dataset Information

3?, 6?-dichloro-5-hydroxy-5?-cholestane facilitates neuronal development through modulating TrkA signaling regulated proteins in primary hippocampal neuron.

Publications

3β, 6β-dichloro-5-hydroxy-5α-cholestane facilitates neuronal development through modulating TrkA signaling regulated proteins in primary hippocampal neuron.

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