Title:Misoprostol Reverse Hippocampal Neuron Cyclooxygenase-2 Downstream Signaling Imbalance in Aluminum-Overload Rats
Volume: 13
Issue: 9
Author(s): Yuanxin Guo, Wenjuan Lei, Jianfeng Wang, Xinyue Hu, Yuling Wei, Chaonan Ji and Junqing Yang*
Affiliation:
- Department of Pharmacology, Chongqing Medical University, Chongqing 400016,China
Keywords:
Alzheimer disease , neurodegeneration, misoprostol, PGE2, PGES, EPs receptor.
Abstract: Although COX-2 inhibition in animal models of neurodegenerative diseases has shown neuroprotection,
recent studies have revealed some serious side effects (ulcers, bleeding, fatal cerebrovascular
diseases etc.) and the limited benefits of COX-2 inhibitors. A more focused approach is necessary
to explore the therapeutic effect of the COX downstream signaling pathway in neurological research.
The aim of this study was to explore the alterations of the PGES-PGE2-EP signal pathway and
the effect of misoprostol on neurodegeneration by chronic aluminum-overload in rats. Adult rats were
treated by intragastric administration of aluminum gluconate. The PGE2 content and expression of PGES and EPs in the
hippocampi of rats were detected using ELISA, q-PCR and Western blot analysis, respectively. The content of malondialdehyde
(MDA) and the activity of superoxide dismutase (SOD) in the rat hippocampi were also detected. The misoprostol
treatment dose-dependently improved spatial learning and memory function as well as healing after hippocampal neuron
damage induced by chronic aluminum-overload in rats. Meanwhile, the administration of misoprostol resulted in a decrease
in the PGE2 level and down-regulation of the mPGES-1, EP2 and EP4 expression levels, while there was a dosedependent
up-regulation of EP3 expression. These results suggest that misoprostol possesses a neuroprotective property,
and the mechanism involves affecting the EP3 level and reducing the endogenous production of PGE2 through a negative
feedback mechanism, increasing the EP3 expression level, decreasing the EP2 and EP4 expression levels, and rebuilding
the mPGES-1-PGE2-EP1-4 signal pathway balance. In this way, misoprostol has a counteractive effect on oxidant stress
and inflammation in the central nervous system. The PGES-PGE2-EPs signaling pathway is a potential therapeutic strategy
for treating neurodegeneration in patients.
