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

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
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Affiliations: Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
Published online on: May 25, 2021 https://doi.org/10.3892/mmr.2021.12168
Article Number: 529
Copyright : © Song et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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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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1	Soria Lopez JA, Gonzalez HM and Leger GC: Alzheimer's disease. Handb Clin Neurol. 167:231–255. 2019. View Article : Google Scholar : PubMed/NCBI
2	Tiwari S, Atluri V, Kaushik A, Yndart A and Nair M: Alzheimer's disease: Pathogenesis, diagnostics, and therapeutics. Int J Nanomedicine. 14:5541–5554. 2019. View Article : Google Scholar : PubMed/NCBI
3	Ferreira-Vieira TH, Guimaraes IM, Silva FR and Ribeiro FM: Alzheimer's disease: Targeting the Cholinergic System. Curr Neuropharmacol. 14:101–115. 2016. View Article : Google Scholar : PubMed/NCBI
4	Parsons MP and Raymond LA: Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron. 82:279–293. 2014. View Article : Google Scholar : PubMed/NCBI
5	Wang R and Reddy PH: Role of glutamate and NMDA receptors in Alzheimer's disease. J Alzheimers Dis. 57:1041–1048. 2017. View Article : Google Scholar : PubMed/NCBI
6	Sanhueza M and Lisman J: The CaMKII/NMDAR complex as a molecular memory. Mol Brain. 6:102013. View Article : Google Scholar : PubMed/NCBI
7	Wang D, Noda Y, Zhou Y, Nitta A, Nabeshima T and Yu Q: Effects of sodium houttuyfonate on phosphorylation of CaMK II, CREB and ERK 1/2 and expression of c-Fos in macrophages. Int Immunopharmacol. 4:1083–1088. 2004. View Article : Google Scholar : PubMed/NCBI
8	Baek A, Park EJ, Kim SY, Nam BG, Kim JH, Jun SW, Kim SH and Cho SR: High-Frequency repetitive magnetic stimulation enhances the expression of brain-derived neurotrophic factor through activation of Ca²⁺-calmodulin-dependent protein kinase II-cAMP-response element-binding protein pathway. Front Neurol. 9:2852018. View Article : Google Scholar : PubMed/NCBI
9	Zhang Z, Cao X, Bao X, Zhang Y, Xu Y and Sha D: Cocaine- and amphetamine-regulated transcript protects synaptic structures in neurons after ischemic cerebral injury. Neuropeptides. 81:1020232020. View Article : Google Scholar : PubMed/NCBI
10	Islam R, Matsuzaki K, Sumiyoshi E, Hossain ME, Hashimoto M, Katakura M, Sugimoto N and Shido O: Theobromine improves working memory by activating the CaMKII/CREB/BDNF pathway in rats. Nutrients. 11:8882019. View Article : Google Scholar : PubMed/NCBI
11	Ko HR, Ahn SY, Chang YS, Hwang I, Yun T, Sung DK, Sung SI, Park WS and Ahn JY: Human UCB-MSCs treatment upon intraventricular hemorrhage contributes to attenuate hippocampal neuron loss and circuit damage through BDNF-CREB signaling. Stem Cell Res Ther. 9:3262018. View Article : Google Scholar : PubMed/NCBI
12	Moir RD, Lathe R and Tanzi RE: The antimicrobial protection hypothesis of Alzheimer's disease. Alzheimers Dement. 14:1602–1614. 2018. View Article : Google Scholar : PubMed/NCBI
13	Rathinam VA and Fitzgerald KA: Inflammasome complexes: Emerging mechanisms and effector functions. Cell. 165:792–800. 2016. View Article : Google Scholar : PubMed/NCBI
14	Man SM and Kanneganti TD: Regulation of inflammasome activation. Immunol Rev. 265:6–21. 2015. View Article : Google Scholar : PubMed/NCBI
15	Olsen I and Singhrao SK: Inflammasome involvement in Alzheimer's disease. J Alzheimers Dis. 54:45–53. 2016. View Article : Google Scholar : PubMed/NCBI
16	Zhao N, Sun C, Zheng M, Liu S and Shi R: Amentoflavone suppresses amyloid β1–42 neurotoxicity in Alzheimer's disease through the inhibition of pyroptosis. Life Sci. 239:1170432019. View Article : Google Scholar : PubMed/NCBI
17	La Rosa F, Saresella M, Marventano I, Piancone F, Ripamonti E, Al-Daghri N, Bazzini C, Zoia CP, Conti E, Ferrarese C and Clerici M: Stavudine reduces NLRP3 inflammasome activation and modulates amyloid-β autophagy. J Alzheimers Dis. 72:401–412. 2019. View Article : Google Scholar : PubMed/NCBI
18	Wang S, Yuan YH, Chen NH and Wang HB: The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in Parkinson's disease. Int Immunopharmacol. 67:458–464. 2019. View Article : Google Scholar : PubMed/NCBI
19	Qiu Z, Lei S, Zhao B, Wu Y, Su W, Liu M, Meng Q, Zhou B, Leng Y and Xia ZY: NLRP3 inflammasome activation-mediated pyroptosis aggravates myocardial ischemia/reperfusion injury in diabetic rats. Oxid Med Cell Longev. 2017:97432802017. View Article : Google Scholar : PubMed/NCBI
20	Hickman S, Izzy S, Sen P, Morsett L and El Khoury J: Microglia in neurodegeneration. Nat Neurosci. 21:1359–1369. 2018. View Article : Google Scholar : PubMed/NCBI
21	Hansen DV, Hanson JE and Sheng M: Microglia in Alzheimer's disease. J Cell Biol. 217:459–472. 2018. View Article : Google Scholar : PubMed/NCBI
22	Orihuela R, McPherson CA and Harry GJ: Microglial M1/M2 polarization and metabolic states. Br J Pharmacol. 173:649–665. 2016. View Article : Google Scholar : PubMed/NCBI
23	Sominsky L, De Luca S and Spencer SJ: Microglia: Key players in neurodevelopment and neuronal plasticity. Int J Biochem Cell Biol. 94:56–60. 2018. View Article : Google Scholar : PubMed/NCBI
24	Wu Y, Dissing-Olesen L, MacVicar BA and Stevens B: Microglia: Dynamic mediators of synapse development and plasticity. Trends Immunol. 36:605–613. 2015. View Article : Google Scholar : PubMed/NCBI
25	Corder G, Castro DC, Bruchas MR and Scherrer G: Endogenous and exogenous opioids in pain. Annu Rev Neurosci. 41:453–473. 2018. View Article : Google Scholar : PubMed/NCBI
26	Takahashi K, Nakagawasai O, Sugawara M, Sato A, Nemoto W, Tadano T and Tan-No K: Kappa opioid receptor agonist administration in olfactory bulbectomized mice restores cognitive impairment through cholinergic neuron activation. Biol Pharm Bull. 41:957–960. 2018. View Article : Google Scholar : PubMed/NCBI
27	D'Hooge R and De Deyn PP: Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev. 36:60–90. 2001. View Article : Google Scholar
28	Garthe A and Kempermann G: An old test for new neurons: Refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis. Front Neurosci. 7:632013. View Article : Google Scholar : PubMed/NCBI
29	Meldrum BS: Glutamate as a neurotransmitter in the brain: Review of physiology and pathology. J Nutr. 130 (Suppl 4S):1007S–1015S. 2000. View Article : Google Scholar : PubMed/NCBI
30	Colombo MN and Francolini M: Glutamate at the vertebrate neuromuscular junction: From modulation to neurotransmission. Cells. 8:9962019. View Article : Google Scholar : PubMed/NCBI
31	Man SM, Karki R and Kanneganti TD: Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 277:61–75. 2017. View Article : Google Scholar : PubMed/NCBI
32	Takemoto-Kimura S, Suzuki K, Horigane SI, Kamijo S, Inoue M, Sakamoto M, Fujii H and Bito H: Calmodulin kinases: Essential regulators in health and disease. J Neurochem. 141:808–818. 2017. View Article : Google Scholar : PubMed/NCBI
33	Waldhoer M, Bartlett SE and Whistler JL: Opioid receptors. Annu Rev Biochem. 73:953–990. 2004. View Article : Google Scholar : PubMed/NCBI
34	Ding YQ, Kaneko T, Nomura S and Mizuno N: Immunohistochemical localization of mu-opioid receptors in the central nervous system of the rat. J Comp Neurol. 367:375–402. 1996. View Article : Google Scholar : PubMed/NCBI
35	Baumann MH, Majumdar S, Le Rouzic V, Hunkele A, Uprety R, Huang XP, Xu J, Roth BL, Pan YX and Pasternak GW: Pharmacological characterization of novel synthetic opioids (NSO) found in the recreational drug marketplace. Neuropharmacology. 134((Pt A)): 101–107. 2018. View Article : Google Scholar : PubMed/NCBI
36	Beck TC, Hapstack MA, Beck KR and Dix TA: Therapeutic potential of kappa opioid agonists. Pharmaceuticals (Basel). 12:952019. View Article : Google Scholar : PubMed/NCBI
37	Wang Q, Sun Y, Li J, Xing W, Zhang S, Gu X, Feng N, Zhao L, Fan R, Wang Y, et al: Quaternary ammonium salt of U50488H, a new κ-opioid receptor agonist, protects rat heart against ischemia/reperfusion injury. Eur J Pharmacol. 737:177–184. 2014. View Article : Google Scholar : PubMed/NCBI
38	Ding S, Xu Z, Yang J, Liu L, Huang X, Wang X and Zhuge Q: The involvement of the decrease of astrocytic Wnt5a in the cognitive decline in minimal hepatic encephalopathy. Mol Neurobiol. 54:7949–7963. 2017. View Article : Google Scholar : PubMed/NCBI
39	Zhang L, Chen ZW, Yang SF, Shaer M, Wang Y, Dong JJ and Jiapaer B: MicroRNA-219 decreases hippocampal long-term potentiation inhibition and hippocampal neuronal cell apoptosis in type 2 diabetes mellitus mice by suppressing the NMDAR signaling pathway. CNS Neurosci Ther. 25:69–77. 2019. View Article : Google Scholar : PubMed/NCBI
40	Shonesy BC, Jalan-Sakrikar N, Cavener VS and Colbran RJ: CaMKII: A molecular substrate for synaptic plasticity and memory. Prog Mol Biol Transl Sci. 122:61–87. 2014. View Article : Google Scholar : PubMed/NCBI
41	Ahmed T and Frey JU: Plasticity-specific phosphorylation of CaMKII, MAP-kinases and CREB during late-LTP in rat hippocampal slices in vitro. Neuropharmacology. 49:477–492. 2005. View Article : Google Scholar : PubMed/NCBI
42	Li X, Sun Y, Jin Q, Song D and Diao Y: Kappa opioid receptor agonists improve postoperative cognitive dysfunction in rats via the JAK2/STAT3 signaling pathway. Int J Mol Med. 44:1866–1876. 2019.PubMed/NCBI