Protective effects of the novel adenosine derivative WS0701 in a mouse model of posttraumatic stress disorder

• Published in: Acta pharmacologica Sinica Vol. 35; no. 1; pp. 24 - 32
• Main Authors: Huang, Zhong-lin, Liu, Rui, Bai, Xiao-yu, Zhao, Gang, Song, Jun-ke, Wu, Song, Du, Guan-hua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2014; Nature Publishing Group
• Subjects: Adenosine - administration & dosage; Adenosine - analogs & derivatives; Adenosine - chemistry; Animals; Bax; Bcl-2; Biomedical and Life Sciences; Biomedicine; Disease Models, Animal; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Immunology; Internal Medicine; Male; Medical Microbiology; Mice; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - chemistry; Original; original-article; Pharmacology/Toxicology; Stress Disorders, Post-Traumatic - metabolism; Stress Disorders, Post-Traumatic - pathology; Stress Disorders, Post-Traumatic - prevention & control; Vaccine; 保护作用; 创伤; 小鼠模型; 应激; 神经细胞凋亡; 腺苷; 衍生物; adenosine; memory deficits; Bcl-2; anxiety; paroxetine; hippocampus; AMG-1; Bax; WS0701; apoptosis; posttraumatic stress disorder; fear
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2013.143

Aim： To investigate the effects of the novel N6-substituted adenosine derivative {（2R,3S,4R,5R）-3,4-dihydroxy-5-[6-[（4-hydroxy-3-methoxybenzyl）amino]-9H-purin-9-yl]tetrahydrofuran-2-yl} methyl decanoate （WS0701） on stress-induced excessive fear, anxiety, and cognitive deficits in a mouse model of posttraumatic stress disorder （PTSD）. Methods： Molecular modeling approach combining quantum-polarized ligand docking （QPLD）, MM/GBSA free-energy calculation and 3D-QSAR analysis was used to evaluate 24 compounds as dual AT1 and ETA receptor antagonists and to reveal their binding modes and structural basis of the inhibitory activity. Pharmacophore-based virtual screening and docking studies were performed to identify more potent dual antagonists. Results： WS0701 administration significantly alleviated fear, anxious behaviors and memory deficits in the mouse model of PTSD. Furthermore, WS0701 administration significantly reduced the stress-induced apoptosis of hippocampal neurons, and increased the Bcl-2/Bax ratio in the hippocampus. The positive control drug paroxetine exerted similar effects on PTSD-like behaviors and hippocampal neuron apoptosis in the mouse model of PTSD, which were comparable to those caused by the high dose of WS0701. Conclusion： WS0701 effectively mitigates stress-induced PTSD-like behaviors in mice, partly via inhibition of neuronal apoptosis in the hippocampus.