κ‑opioid receptor agonist U50488H attenuates postoperative cognitive dysfunction of cardiopulmonary bypass rats through the PI3K/AKT/Nrf2/HO‑1 pathway

Fan,Jianing; Li,Long; Qu,Pengxia; Diao,Yugang; Sun,Yingjie

doi:10.3892/mmr.2021.11933

κ‑opioid receptor agonist U50488H attenuates postoperative cognitive dysfunction of cardiopulmonary bypass rats through the PI3K/AKT/Nrf2/HO‑1 pathway

Authors:
- Jianing Fan
- Long Li
- Pengxia Qu
- Yugang Diao
- Yingjie Sun
View Affiliations

Affiliations: Postgraduate Training Base of The General Hospital of Northern Theater Command, Jinzhou Medical University, Jinzhou, Liaoning 121013, P.R. China, Department of Anesthesiology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
Published online on: February 23, 2021 https://doi.org/10.3892/mmr.2021.11933
Article Number: 293
Copyright: © Fan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Postoperative cognitive dysfunction (POCD) is a common complication following cardiopulmonary bypass (CPB). U50488H, a κ‑opioid receptor (KOR) agonist, can specifically activate KORs on hippocampal nerve cells, resulting in neuroprotective effects. The present study established a CPB rat model, observed the protective effect of U50488H on CPB‑induced POCD and brain damage and explored the regulatory mechanism of the PI3K/AKT/nuclear factor erythroid 2‑related factor 2 (Nrf2)/heme oxygenase (HO)‑1 pathway. Sprague‑Dawley rats were divided into the following groups: Sham operation (Sham group), CPB (CPB group), KOR agonist (U50488H) + CPB (U50488H group), CPB + U50488H + HO‑1 antagonist (ZnPP‑IX; ZnPP group) and CPB + U50488H + PI3K antagonist (LY294002; LY294002 group), with 10 rats in each group. Neurological scores and the Morris water maze test were used to evaluate cognitive function; hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed to observe hippocampal neuron damage in rats. Immunofluorescence was used to detect reactive oxygen species, glial fibrillary acidic protein and Nrf2 expression in the hippocampus. Enzyme‑linked immunosorbent assays were used to detect inflammatory and oxidative stress factors. Western blotting was used to examine the expression of PI3K/AKT/Nrf2/HO‑1‑related proteins. It was demonstrated that U50488H significantly reduced the neural function score of rats with POCD induced by CPB, relieved cognitive dysfunction, reduced hippocampal neuron damage, inhibited the rate of apoptosis, repaired oxidative stress injury and protected against brain damage caused by CPB. In addition, U50488H could promote Nrf2 entry into the nucleus and upregulate HO‑1 and thioredoxin 1 (Trx1) expression. In CPB rats treated with PI3K inhibitors, less Nrf2 was detected in the nucleus and HO‑1 and Trx‑1 expression levels were reduced in the nucleus. Therefore, U50488H, a KOR agonist, can activate Nrf2/HO‑1 via the PI3K/AKT pathway to improve cognitive function and reduce brain damage in CPB rats.

View Figures

View References

1	Martin J and Cheng DC: Neurologic complications after cardiac surgery: Stroke, Delirium, Postoperative Cognitive Dysfunction, and Peripheral Neuropathy. Evidence-Based Practice in Perioperative Cardiac Anesthesia and Surgery. Springer; pp. 619–636. 2020
2	Keith JR, Puente AE, Malcolmson KL, Tartt S, Coleman AE and Marks HF Jr: Assessing postoperative cognitive change after cardiopulmonary bypass surgery. Neuropsychology. 16:411–421. 2002. View Article : Google Scholar : PubMed/NCBI
3	Kumpaitiene B, Svagzdiene M, Sirvinskas E, Adomaitiene V, Petkus V, Zakelis R, Krakauskaite S, Chomskis R, Ragauskas A and Benetis R: Cerebrovascular autoregulation impairments during cardiac surgery with cardiopulmonary bypass are related to postoperative cognitive deterioration: Prospective observational study. Minerva Anestesiol. 85:594–603. 2019. View Article : Google Scholar : PubMed/NCBI
4	Chen K, Sun Y, Dong W, Zhang T, Zhou N, Yu W, Diao Y, Guo S and Tian Y: Activated A7nachr improves postoperative cognitive dysfunction and intestinal injury induced by cardiopulmonary bypass in rats: Inhibition of the proinflammatory response through the Th17 immune response. Cell Physiol Biochem. 46:1175–1188. 2018. View Article : Google Scholar : PubMed/NCBI
5	Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, Eguchi M, Wada Y, Kumagai Y and Yamamoto M: The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol. 29:493–502. 2009. View Article : Google Scholar : PubMed/NCBI
6	Takaya K, Suzuki T, Motohashi H, Onodera K, Satomi S, Kensler TW and Yamamoto M: Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Radic Biol Med. 53:817–827. 2012. View Article : Google Scholar : PubMed/NCBI
7	Chen HH, Chen YT, Huang YW, Tsai HJ and Kuo CC: 4-Ketopinoresinol, a novel naturally occurring ARE activator, induces the Nrf2/HO-1 axis and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling. Free Radic Biol Med. 52:1054–1066. 2012. View Article : Google Scholar : PubMed/NCBI
8	Netto MB, de Oliveira Junior AN, Goldim M, Mathias K, Fileti ME, da Rosa N, Laurentino AO, de Farias BX, Costa AB, Rezin GT, et al: Oxidative stress and mitochondrial dysfunction contributes to postoperative cognitive dysfunction in elderly rats. Brain Behav Immun. 73:661–669. 2018. View Article : Google Scholar : PubMed/NCBI
9	Narasimhan M, Patel D, Vedpathak D, Rathinam M, Henderson G and Mahimainathan L: Identification of novel microRNAs in post-transcriptional control of Nrf2 expression and redox homeostasis in neuronal, SH-SY5Y cells. PLoS One. 7:e511112012. View Article : Google Scholar : PubMed/NCBI
10	Hong-Qiang H, Mang-Qiao S, Fen X, Shan-Shan L, Hui-Juan C, Wu-Gang H, Wen-Jun Y and Zheng-Wu P: Sirt1 mediates improvement of isoflurane-induced memory impairment following hyperbaric oxygen preconditioning in middle-aged mice. Physiol Behav. 195:1–8. 2018. View Article : Google Scholar : PubMed/NCBI
11	Gozzelino R, Jeney V and Soares MP: Mechanisms of cell protection by heme oxygenase-1. Annu Rev Pharmacol Toxicol. 50:323–354. 2010. View Article : Google Scholar : PubMed/NCBI
12	Yu M, Wang J, Fang Q, Liu P, Chen S, Zhe N, Lin X, Zhang Y, Zhao J and Zhou Z: High expression of heme oxygenase-1 in target organs may attenuate acute graft-versus-host disease through regulation of immune balance of TH17/Treg. Transpl Immunol. 37:10–17. 2016. View Article : Google Scholar : PubMed/NCBI
13	Wu B, Song HL, Yang Y, Yin ML, Zhang BY, Cao Y, Dong C and Shen ZY: Improvement of liver transplantation outcome by heme oxygenase-1-transduced bone marrow mesenchymal stem cells in rats. Stem Cells Int. 2016:92350732016. View Article : Google Scholar : PubMed/NCBI
14	Billings FT IV, Yu C, Byrne JG, Petracek MR and Pretorius M: Heme oxygenase-1 and acute kidney injury following cardiac surgery. Cardiorenal Med. 4:12–21. 2014. View Article : Google Scholar : PubMed/NCBI
15	Lever JM, Boddu R, George JF and Agarwal A: Heme oxygenase-1 in kidney health and disease. Antioxid Redox Signal. 25:165–183. 2016. View Article : Google Scholar : PubMed/NCBI
16	Chang M, Xue J, Sharma V and Habtezion A: Protective role of hemeoxygenase-1 in gastrointestinal diseases. Cell Mol Life Sci. 72:1161–1173. 2015. View Article : Google Scholar : PubMed/NCBI
17	Hu L, Chen W, Tian F, Yuan C, Wang H and Yue H: Neuroprotective role of fucoxanthin against cerebral ischemic/reperfusion injury through activation of Nrf2/HO-1 signaling. Biomed Pharmacother. 106:1484–1489. 2018. View Article : Google Scholar : PubMed/NCBI
18	Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J and Motterlini R: Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J. 371:887–895. 2003. View Article : Google Scholar : PubMed/NCBI
19	Fang J, Wang H, Zhou J, Dai W, Zhu Y, Zhou Y, Wang X and Zhou M: Baicalin provides neuroprotection in traumatic brain injury mice model through Akt/Nrf2 pathway. Drug Des Devel Ther. 12:2497–2508. 2018. View Article : Google Scholar : PubMed/NCBI
20	Wang P, Cao J, Liu N, Ma L, Zhou X, Zhang H and Wang Y: Protective effects of edaravone in adult rats with surgery and lipopolysaccharide administration-induced cognitive function impairment. PLoS One. 11:e01537082016. View Article : Google Scholar : PubMed/NCBI
21	Meng X, Wang M, Sun G, Ye J, Zhou Y, Dong X, Wang T, Lu S and Sun X: Attenuation of Aβ25-35-induced parallel autophagic and apoptotic cell death by gypenoside XVII through the estrogen receptor-dependent activation of Nrf2/ARE pathways. Toxicol Appl Pharmacol. 279:63–75. 2014. View Article : Google Scholar : PubMed/NCBI
22	Zou Y, Hong B, Fan L, Zhou L, Liu Y, Wu Q, Zhang X and Dong M: Protective effect of puerarin against beta-amyloid-induced oxidative stress in neuronal cultures from rat hippocampus: Involvement of the GSK-3β/Nrf2 signaling pathway. Free Radic Res. 47:55–63. 2013. View Article : Google Scholar : PubMed/NCBI
23	Chunhua C, Chunhua X, Megumi S and Renyu L: Kappa opioid receptor agonist and brain ischemia. Transl Perioper Pain Med. 1:27–34. 2014.PubMed/NCBI
24	Charron C, Messier C and Plamondon H: Neuroprotection and functional recovery conferred by administration of kappa- and delta 1-opioid agonists in a rat model of global ischemia. Physiol Behav. 93:502–511. 2008. View Article : Google Scholar : PubMed/NCBI
25	Sun Y, Song D, Wang M, Chen K and Zhang T: α7 nicotinic acetylcholine receptor agonist attenuates the cerebral injury in a rat model of cardiopulmonary bypass by activating the Akt/GSK3β pathway. Mol Med Rep. 16:7979–7986. 2017. View Article : Google Scholar : PubMed/NCBI
26	Longa EZ, Weinstein PR, Carlson S and Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20:84–91. 1989. View Article : Google Scholar : PubMed/NCBI
27	Mackensen GB, Sato Y, Nellgård B, Pineda J, Newman MF, Warner DS and Grocott HP: Cardiopulmonary bypass induces neurologic and neurocognitive dysfunction in the rat. Anesthesiology. 95:1485–1491. 2001. View Article : Google Scholar : PubMed/NCBI
28	Johnsson P, Lundqvist C, Lindgren A, Ferencz I, Alling C and Ståhl E: Cerebral complications after cardiac surgery assessed by S-100 and NSE levels in blood. J Cardiothorac Vasc Anesth. 9:694–699. 1995. View Article : Google Scholar : PubMed/NCBI
29	Chen K, Li G, Geng F, Zhang Z, Li J, Yang M, Dong L and Gao F: Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats. Apoptosis. 19:946–957. 2014. View Article : Google Scholar : PubMed/NCBI
30	Li X, Zhang J, Zhu X, Wang P, Wang X and Li D: Progesterone reduces inflammation and apoptosis in neonatal rats with hypoxic ischemic brain damage through the PI3K/Akt pathway. Int J Clin Exp Med. 8:81972015.PubMed/NCBI
31	Pachori AS, Smith A, McDonald P, Zhang L, Dzau VJ and Melo LG: Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway. J Mol Cell Cardiol. 43:580–592. 2007. View Article : Google Scholar : PubMed/NCBI
32	Zhang L, Qu Y, Tang J, Chen D, Fu X, Mao M and Mu D: PI3K/Akt signaling pathway is required for neuroprotection of thalidomide on hypoxic-ischemic cortical neurons in vitro. Brain Res. 1357:157–165. 2010. View Article : Google Scholar : PubMed/NCBI
33	Trushina E and McMurray C: Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience. 145:1233–1248. 2007. View Article : Google Scholar : PubMed/NCBI
34	Schurr A: Lactate, glucose and energy metabolism in the ischemic brain (Review). Int J Mol Med. 10:131–136. 2002.PubMed/NCBI
35	Arrica M and Bissonnette B: Therapeutic hypothermia. Semin Cardiothorac Vasc Anesth. 11:6–15. 2007. View Article : Google Scholar : PubMed/NCBI
36	Dai H, Wang P, Mao H, Mao X, Tan S and Chen Z: Dynorphin activation of kappa opioid receptor protects against epilepsy and seizure-induced brain injury via PI3K/Akt/Nrf2/HO-1 pathway. Cell Cycle. 18:226–237. 2019. View Article : Google Scholar : PubMed/NCBI
37	Kennedy DO and Haskell CF: Cerebral blood flow and behavioural effects of caffeine in habitual and non-habitual consumers of caffeine: A near infrared spectroscopy study. Biol Psychol. 86:298–306. 2011. View Article : Google Scholar : PubMed/NCBI
38	Neema PK, Dharan BS, Singha SK, Sethuraman M and Rathod RC: Entropy score, patent ductus arteriosus (PDA), and cardiopulmonary bypass (CPB): Ligation of PDA on CPB can compromise cerebral blood flow. Ann Card Anaesth. 14:203–205. 2011. View Article : Google Scholar : PubMed/NCBI
39	Gottesman RP, Grega MA, McKhann GM and Selnes OA: Neurological complications of cardiac surgery: Stroke, encephalopathy, and cognitive decline. Brain disorders in critical illness: Mechanisms, diagnosis, and treatment. Camb Univ Press; pp. 410–418. 2011
40	Simonin F, Gavériaux-Ruff C, Befort K, Matthes H, Lannes B, Micheletti G, Mattéi MG, Charron G, Bloch B and Kieffer B: kappa-opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci USA. 92:7006–7010. 1995. View Article : Google Scholar : PubMed/NCBI
41	Silvia RC, Slizgi GR, Ludens JH and Tang AH: Protection from ischemia-induced cerebral edema in the rat by U-50488H, a kappa opioid receptor agonist. Brain Res. 403:52–57. 1987. View Article : Google Scholar : PubMed/NCBI
42	Cai Z and Ratka A: Opioid system and Alzheimer's disease. Neuromolecular Med. 14:91–111. 2012. View Article : Google Scholar : PubMed/NCBI
43	Rácz B and Halasy K: Kappa opioid receptor is expressed by somatostatin- and neuropeptide Y-containing interneurons in the rat hippocampus. Brain Res. 931:50–55. 2002. View Article : Google Scholar : PubMed/NCBI
44	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