title: PGE2-EP3 signaling pathway contributes to protective effects of misoprostol on cerebral injury in APP/PS1 mice.
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.
authors.affiliation: Department of Pharmacology, Chongqing Medical University, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Pharmacology, Chongqing Medical University, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
authors.forename: Chaonan
authors.initials: C
authors.lastname: Ji
authors.affiliation: Department of Pharmacology, Chongqing Medical University, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, Chongqing Medical University, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Chongqing Medical University, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Kuang
authors.affiliation: Department of Pharmacology, Chongqing Medical University, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
authors.forename: Shaoshan
authors.initials: S
authors.lastname: Mai
authors.affiliation: Department of Pharmacology, Chongqing Medical University, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Chongqing Medical University, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
authors.forename: Junqing
authors.initials: J
authors.lastname: Yang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016595:Misoprostol / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; C545648:Ptger3 protein, mouse; D058308:Receptors, Prostaglandin E, EP3 Subtype; D016595:Misoprostol; D015232:Dinoprostone
keywords: APP/PS1; Alzheimer’s disease; mPGES-1 - PGE2 - EP signaling pathway; misoprostol; oxidative stress