Oncotarget

Research Papers:

PGE2-EP3 signaling pathway contributes to protective effects of misoprostol on cerebral injury in APP/PS1 mice

Xiaoyan Tian, Chaonan Ji, Ying Luo, Yang Yang, Shengnan Kuang, Shaoshan Mai, Jie Ma and Junqing Yang _

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Oncotarget. 2016; 7:25304-25314. https://doi.org/10.18632/oncotarget.8284

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Abstract

Xiaoyan Tian1,*, Chaonan Ji1,*, Ying Luo1, Yang Yang1, Shengnan Kuang1, Shaoshan Mai1, Jie Ma1, Junqing Yang1

1Department of Pharmacology, Chongqing Medical University, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China

*Co-first authors

Correspondence to:

Junqing Yang, email: [email protected]

Keywords: Alzheimer’s disease, misoprostol, APP/PS1, mPGES-1 - PGE2 - EP signaling pathway, oxidative stress

Received: December 17, 2015     Accepted: March 07, 2016     Published: March 23, 2016

ABSTRACT

Epidemiological studies indicate chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the enzymatic activity of the inflammatory cyclooxygenases (COX), reduces the risk of developing Alzheimer’s disease (AD) in normal aging populations. Considering multiple adverse side effects of NSAIDs, findings suggest that COX downstream prostaglandin signaling function in the pre-clinical development of AD. Our previous study found that misoprostol, a synthetic prostaglandin E2 (PGE2) receptor agonist, has neuroprotection against brain injury induced by chronic aluminum overload. Here, we investigated the neuroprotective effects and mechanisms of misoprostol on neurodegeneration in overexpressing both amyloid precursor protein (APP) and mutant presenilin 1 (PS1) mice. Here were young group, elderly group, APP/PS1 group and misoprostol-treated group. Mice in misoprostol-treated group were administrated with misoprostol (200 μg·kg−1·d−1, p.o.) five days a week for 20 weeks. The spatial learning and memory function was impaired and karyopycnosis of hippocampal and cortical neurons was observed; amyloid beta (Aβ) deposition was increased; superoxide dismutase (SOD) activity was decreased and malondialdehyde (MDA) content was increased in APP/PS1 mice. However, misoprostol could significantly blunte these changes in APP/PS1 mic. Moreover, the expressions of microsomal PGE2 synthase (mPGES-1), PGE2, PGE2 receptor (EP) 2 and EP4 were increased and EP3 expression was decreased in APP/PS1 mice, while misoprostol reversed these changes. Our present experimental results indicate that misoprostol has a neuroprotective effect on brain injury and neurodegeneration of APP/PS1 mice and that the activation of PGE2-EP3 signaling and inhibition of oxidative stress contribute to the neuroprotective mechanisms of misoprostol.


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