Inhibitory effect of PDE2 on inflammation and apoptosis in cerebral ischemia‑reperfusion injury

Wan,Ding; Wang,Xiaoyan; Feng,Jin; Wang,Peng; Xu,Hua

doi:10.3892/ijmm.2022.5165

August-2022 Volume 50 Issue 2

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August-2022 Volume 50 Issue 2

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Article Open Access

Inhibitory effect of PDE2 on inflammation and apoptosis in cerebral ischemia‑reperfusion injury

Authors:
- Ding Wan
- Xiaoyan Wang
- Jin Feng
- Peng Wang
- Hua Xu
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Affiliations: Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China, Department of Hospital Infection Management, Zhongning County People's Hospital, Zhongwei, Ningxia 751200, P.R. China, Ningxia Key Laboratory of Cerebro Cranial Disease, Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China, Department of Nursing, Wuxi Higher Health Vocational Technology School, Wuxi, Jiangsu 214028, P.R. China

Copyright: © Wan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 109
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Published online on: June 24, 2022

https://doi.org/10.3892/ijmm.2022.5165
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Abstract

Cerebral ischemia‑reperfusion injury (CIRI) is associated with high morbidity and mortality rates and its pathogenesis is complex. Phosphodiesterase 2 (PDE2) has been proposed to exert a protective effect, although, to the to the best of the authors' knowledge, its role in CIRI has yet to be reported. Therefore, the aim of the present study was to investigate the role of PDE2 in CIRI. To meet this aim, a middle cerebral artery occlusion (MCAO) model was established in mice. After having successfully modeled the MCAO, the mice were treated with the PDE2 inhibitor Bay‑607550 and the expression level of PDE2 was detected using reverse transcription‑quantitative (RT‑q) PCR and western blot analysis. Histopathology of the brain was assessed using hematoxylin and eosin staining. The proportions of dry and wet tissue in brain were recorded and the cerebral ischemia area was assessed using 2,3,5‑triphenyltetrazolium chloride staining. RT‑qPCR was also used to measure the expression levels of inflammatory factors. The expression of ionized calcium binding adaptor molecule 1, a marker of microglia activation, was detected by immunofluorescence assay, western blotting and RT‑qPCR. Western blotting was used to detect the expression levels of P65 and NF‑κB inhibitor α and their phosphorylated forms. The levels of apoptosis were subsequently determined using TUNEL and western blot analysis. SH‑SY5Y cells were induced by oxygen‑glucose deprivation (OGD) and the expression levels of PDE2 were subsequently detected. Cell transfection was used to interfere with the expression of PDE2 and the regulation of PDE2 upon OGD/reoxygenation (OGD/R)‑induced inflammation and apoptosis was further detected in cell experiments. Finally, western blot analysis was used to detect the expression of protein kinase A (PKA) downstream of PDE2 in vivo and in vitro. The expression levels of PDE2 were found to be significantly increased in the MCAO model mice. Following treatment with Bay‑607550, the condition of the brain nerve cells was improved with respect to the levels of cerebral ischemia, inflammation and apoptosis. The results of the in vitro cell experiments were found to be consistent with those of the in vivo animal experiments. Furthermore, the western blotting experiments suggested that the above‑mentioned regulation of PDE2 may be achieved via regulating PKA. Taken together, the present study has shown that inhibition of PDE2 led to a reduction in inflammation and apoptosis during CIRI through regulating PKA.

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1	Shin TH, Lee DY, Basith S, Manavalan B, Paik MJ, Rybinnik I, Mouradian MM, Ahn JH and Lee G: Metabolome changes in cerebral ischemia. Cells. 9:16302020. View Article : Google Scholar :
2	Wang H, Chen S, Zhang Y, Xu H and Sun H: Electroacupuncture ameliorates neuronal injury by Pink1/Parkin-mediated mitophagy clearance in cerebral ischemia-reperfusion. Nitric Oxide. 91:23–34. 2019. View Article : Google Scholar : PubMed/NCBI
3	Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, Li CY and Li CJ: Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem. 46:1650–1667. 2018. View Article : Google Scholar : PubMed/NCBI
4	Weber S, Zeller M, Guan K, Wunder F, Wagner M and El-Armouche A: PDE2 at the crossway between cAMP and cGMP signalling in the heart. Cell Signal. 38:76–84. 2017. View Article : Google Scholar : PubMed/NCBI
5	He Y, Huang Y, Mai C, Pan H, Luo HB, Liu L and Xie Y: The immunomodulatory role of PDEs inhibitors in immune cells: Therapeutic implication in rheumatoid arthritis. Pharmacol Res. 161:1051342020.2020. View Article : Google Scholar : PubMed/NCBI
6	Maurice DH, Ke H, Ahmad F, Wang Y, Chung J and Manganiello VC: Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 13:290–314. 2014. View Article : Google Scholar : PubMed/NCBI
7	Sadek MS, Cachorro E, El-Armouche A and Kämmerer S: Therapeutic implications for PDE2 and cGMP/cAMP mediated crosstalk in cardiovascular diseases. Int J Mol Sci. 21:74622020. View Article : Google Scholar :
8	Zhou Y, Li J, Yuan H, Su R, Huang Y, Huang Y, Li Z, Wu Y, Luo H, Zhang C and Huang L: Design, synthesis, and evaluation of dihydropyranopyrazole derivatives as novel PDE2 inhibitors for the treatment of Alzheimer's disease. Molecules. 26:30342021. View Article : Google Scholar : PubMed/NCBI
9	Chen L, Liu K, Wang Y, Liu N, Yao M, Hu J, Wang G, Sun Y and Pan J: Phosphodiesterase-2 inhibitor reverses post-traumatic stress induced fear memory deficits and behavioral changes via cAMP/cGMP pathway. Eur J Pharmacol. 891:1737682021. View Article : Google Scholar
10	Ruan L, Du K, Tao M, Shan C, Ye R, Tang Y, Pan H, Lv J, Zhang M and Pan J: Phosphodiesterase-2 inhibitor bay 60-7550 ameliorates abeta-induced cognitive and memory impairment via regulation of the HPA axis. Front Cell Neurosci. 13:4322019. View Article : Google Scholar
11	Soares LM, Meyer E, Milani H, Steinbusch HW, Prickaerts J and de Oliveira RM: The phosphodiesterase type 2 inhibitor BAY 60-7550 reverses functional impairments induced by brain ischemia by decreasing hippocampal neurodegeneration and enhancing hippocampal neuronal plasticity. Eur J Neurosci. 45:510–520. 2017. View Article : Google Scholar
12	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
13	Kokkonen K and Kass DA: Nanodomain regulation of cardiac cyclic nucleotide signaling by phosphodiesterases. Annu Rev Pharmacol Toxicol. 57:455–479. 2017. View Article : Google Scholar
14	Francis SH, Blount MA and Corbin JD: Mammalian cyclic nucleotide phosphodiesterases: Molecular mechanisms and physiological functions. Physiol Rev. 91:651–690. 2011. View Article : Google Scholar : PubMed/NCBI
15	Xu B, Xu J, Cai N, Li M, Liu L, Qin Y, Li X and Wang H: Roflumilast prevents ischemic stroke-induced neuronal damage by restricting GSK3beta-mediated oxidative stress and IRE1alpha/TRAF2/JNK pathway. Free Radic Biol Med. 163:281–296. 2021. View Article : Google Scholar
16	Moretti R, Leger PL, Besson VC, Csaba Z, Pansiot J, Di Criscio L, Gentili A, Titomanlio L, Bonnin P, Baud O and Charriaut-Marlangue C: Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain. J Neuroinflammation. 13:952016. View Article : Google Scholar : PubMed/NCBI
17	Yoshida H, Ashikawa Y, Itoh S, Nakagawa T, Asanuma A, Tanabe S, Inoue Y and Hidaka H: K-134, a phosphodiesterase 3 inhibitor, prevents brain damage by inhibiting thrombus formation in a rat cerebral infarction model. PLoS One. 7:e464322012. View Article : Google Scholar : PubMed/NCBI
18	Redondo M, Zarruk JG, Ceballos P, Pérez DI, Pérez C, Perez-Castillo A, Moro MA, Brea J, Val C, Cadavid MI, et al: Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model. Eur J Med Chem. 47:175–185. 2012. View Article : Google Scholar
19	Bender AT and Beavo JA: Specific localized expression of cGMP PDEs in Purkinje neurons and macrophages. Neurochem Int. 45:853–857. 2004. View Article : Google Scholar : PubMed/NCBI
20	Sanders O: Sildenafil for the treatment of Alzheimer's disease: A systematic review. J Alzheimers Dis Rep. 4:91–106. 2020. View Article : Google Scholar : PubMed/NCBI
21	Orellana-Urzua S, Rojas I, Libano L and Rodrigo R: Pathophysiology of ischemic stroke: Role of oxidative stress. Curr Pharm Des. 26:4246–4260. 2020. View Article : Google Scholar : PubMed/NCBI
22	Polderman KH: Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med. 37:S186–S202. 2009. View Article : Google Scholar : PubMed/NCBI
23	Li H, Wang J, Wang P, Rao Y and Chen L: Resveratrol reverses the synaptic plasticity deficits in a chronic cerebral hypoperfusion rat model. J Stroke Cerebrovasc Dis. 25:122–128. 2016. View Article : Google Scholar
24	Liu Y, Zhang J, Zan J, Zhang F, Liu G and Wu A: Lidocaine improves cerebral ischemia-reperfusion injury in rats through cAMP/PKA signaling pathway. Exp Ther Med. 20:495–499. 2020. View Article : Google Scholar : PubMed/NCBI
25	Hu X, Li S, Doycheva DM, Huang L, Lenahan C, Liu R, Huang J, Gao L, Tang J, Zuo G and Zhang JH: Rh-CSF1 attenuates oxidative stress and neuronal apoptosis via the CSF1R/PLCG2/PKA/UCP2 signaling pathway in a rat model of neonatal HIE. Oxid Med Cell Longev. 2020:68015872020. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Inhibitory effect of PDE2 on inflammation and apoptosis in cerebral ischemia‑reperfusion injury

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