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: Male mice underwent a conditioned foot shock and single prolonged stress procedure to induce PTSD. Contextual/cued fear, elevated plus-maze, open field and novel object recognition tests were conduced to assess PTSD-like behaviors. From d 1, the mice were orally administered WS0701 (7.5, 15, or 30 mg·kg(-1)·d(-1)) or paroxetine (10 mg·kg(-1)·d(-1)) for two weeks. Apoptosis of hippocampal neurons was detected using flow cytometry and TUNEL staining, and expression of Bcl-2 and Bax in the hippocampus was measured with Western boltting and qPCR assays.
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.