κ‑opioid receptor agonist, U50488H, inhibits pyroptosis through NLRP3 via the Ca<sup>2+</sup>/CaMKII/CREB signaling pathway and improves synaptic plasticity in APP/PS1 mice

Song,Xiaofu; Cui,Zhiqiang; He,Jiahuan; Yang,Tuo; Sun,Xiaohong

doi:10.3892/mmr.2021.12168

July-2021 Volume 24 Issue 1

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July-2021 Volume 24 Issue 1

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κ‑opioid receptor agonist, U50488H, inhibits pyroptosis through NLRP3 via the Ca²⁺/CaMKII/CREB signaling pathway and improves synaptic plasticity in APP/PS1 mice

Authors:
- Xiaofu Song
- Zhiqiang Cui
- Jiahuan He
- Tuo Yang
- Xiaohong Sun
View Affiliations / Copyright

Affiliations: Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China

Copyright: © Song et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
Article Number: 529
|
Published online on: May 25, 2021

https://doi.org/10.3892/mmr.2021.12168
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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder with slow onset in most cases. Clinically, dementia associated with AD is characterized by memory disorders, aphasia, executive dysfunction and personality and behavior changes. Currently, treatment strategies attempt to reduce certain symptoms, however there is no cure for AD. The aim of the present study was to identify a novel treatment strategy for AD. Thus, the protective effects of a κ‑opioid receptor (KOR) agonist, U50488H on neural damage in AD mice were investigated. The underlying mechanism of the Ca²⁺/calcium/calmodulin‑dependent protein kinase II/cyclic adenosine monophosphate‑response element binding protein (Ca²⁺/CaMKII/CREB) signaling pathway was evaluated. Amyloid precursor protein (APP)/presenilin‑1 (PS1) mice were treated subcutaneously with a KOR agonist for 28 days. The learning and memory abilities of the APP/PS1 mice were evaluated using the Morris water maze test. Damage to hippocampal neurons was assessed using hematoxylin and eosin staining. Inflammatory factors and brain injury markers were detected using ELISA. Neurons were examined using immunofluorescence and dendritic spines were observed using Golgi‑Cox staining. Western blotting was used to detect NOD‑, LRR‑ and pyrin domain‑containing protein 3, microglial ptosis and the Ca²⁺/CaMKII/CREB‑related protein pathway. The KOR agonist significantly improved the brain injury observed in APP/PS1 mice, inhibited microglia pyroptosis and improved the synaptic plasticity of APP/PS1 mice, which was reversed by a KOR antagonist. Thus, the KOR agonist improved the symptoms of APP/PS1 mice by inhibiting the Ca²⁺/CaMKII/CREB signaling pathway.

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