Dexmedetomidine Attenuates Isoflurane-induced Neuroapoptosis Through the MiR-137/GSK-3β Pathway in the Developing Rat Hippocampus

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 May 30

PMID 38813218

Authors

Xueyuan Hu

Zihan Sun

Wenjing Wang

Gong Xiao

Quanlin Yu

Liang Chi

Huanqi Liu

Affiliations

Soon will be listed here.

Abstract

Long-term isoflurane inhalation has been reported to induce hippocampal apoptosis in young animals, whereas dexmedetomidine (DEX) can reduce isoflurane-induced neuronal apoptosis. The neuroprotective effect of miR-137 has been reported before, however, the effect of on isoflurane triggered neuronal apoptosis, and whether miR-137 is involved in the neuroprotection of DEX remain unclear. To investigate these doubts, we established an isoflurane exposure model in postnatal day 7 (P7) Sprague‒Dawley rats and the PC12 cells, containing a control group (CON), isoflurane group (ISO), DEX group (DEX) and DEX pretreatment group (DEX + ISO). We first confirmed that DEX attenuates isoflurane-induced hippocampal apoptosis. And we found DEX increased miR-137 and attenuated GSK-3β levels in the DEX and DEX + ISO groups in the hippocampus and PC12 cells. In addition, the regulative relationship of miR-137 and GSK-3β was confirmed using the TargetScan tool and dual-luciferase reporter assay. Moreover, miR-137 overexpression inhibited GSK-3β and increased its downstream gene β-catenin, whereas knockdown of miR-137 changed the GSK-3β and β-catenin expression oppositely. Upregulation of miR-137 increased the apoptosis-related genes and decreased the anti-apoptosis gene; however, knockdown of miR-137 produced the opposite results. This study suggested that DEX attenuated isoflurane-induced neuroapoptosis by upregulating the miR-137 mediated GSK-3β/β-catenin pathway in the developing rat hippocampus.

References

Liu J, Li L, Xie P, Zhao X, Shi D, Zhang Y . Sevoflurane induced neurotoxicity in neonatal mice links to a GSK3β/Drp1-dependent mitochondrial fission and apoptosis. Free Radic Biol Med. 2022; 181:72-81. DOI: 10.1016/j.freeradbiomed.2022.01.031. View

Carmichael J, Sugars K, Bao Y, Rubinsztein D . Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. J Biol Chem. 2002; 277(37):33791-8. DOI: 10.1074/jbc.M204861200. View

Lee R, Feinbaum R, Ambros V . The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993; 75(5):843-54. DOI: 10.1016/0092-8674(93)90529-y. View

Huang C, Zhang X, Zheng J, Chen C, Chen Y, Yi J . Upregulation of miR-137 protects anesthesia-induced hippocampal neurodegeneration. Int J Clin Exp Pathol. 2014; 7(8):5000-7. PMC: 4152061. View

Monga S, Monga H, Tan X, Mule K, Pediaditakis P, Michalopoulos G . Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. Gastroenterology. 2003; 124(1):202-16. DOI: 10.1053/gast.2003.50000. View

Li Y, Zeng M, Chen W, Liu C, Wang F, Han X . Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by preserving PI3K/Akt pathway in the hippocampus of neonatal rats. PLoS One. 2014; 9(4):e93639. PMC: 3990549. DOI: 10.1371/journal.pone.0093639. View

Xie Z, Culley D, Dong Y, Zhang G, Zhang B, Moir R . The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo. Ann Neurol. 2008; 64(6):618-27. PMC: 2612087. DOI: 10.1002/ana.21548. View

Hu X, Chi Q, Wang D, Chi X, Teng X, Li S . Hydrogen sulfide inhalation-induced immune damage is involved in oxidative stress, inflammation, apoptosis and the Th1/Th2 imbalance in broiler bursa of Fabricius. Ecotoxicol Environ Saf. 2018; 164:201-209. DOI: 10.1016/j.ecoenv.2018.08.029. View

Qian X, Zhang W, Liu M, Zhou Y, Zhang J, Han L . Dexmedetomidine improves early postoperative cognitive dysfunction in aged mice. Eur J Pharmacol. 2014; 746:206-12. DOI: 10.1016/j.ejphar.2014.11.017. View

10.

Li W, Bai X, Guo R, Xing X, Zhang H, Gao X . MicroRNA-137 Inhibits Esophageal Squamous Cell Carcinoma by Downregulating DAAM1. Protein Pept Lett. 2022; 29(10):882-890. DOI: 10.2174/0929866529666220819123149. View

11.

Farr S, Ripley J, Sultana R, Zhang Z, Niehoff M, Platt T . Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease. Free Radic Biol Med. 2013; 67:387-95. PMC: 3945161. DOI: 10.1016/j.freeradbiomed.2013.11.014. View

12.

Visvanathan J, Lee S, Lee B, Lee J, Lee S . The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev. 2007; 21(7):744-9. PMC: 1838526. DOI: 10.1101/gad.1519107. View

13.

Zhu J, Xu X, Liang Y, Zhu R . Downregulation of microRNA-15b-5p Targeting the Akt3-Mediated GSK-3/-Catenin Signaling Pathway Inhibits Cell Apoptosis in Parkinson's Disease. Biomed Res Int. 2021; 2021:8814862. PMC: 7806375. DOI: 10.1155/2021/8814862. View

14.

Mahmoudi E, Cairns M . MiR-137: an important player in neural development and neoplastic transformation. Mol Psychiatry. 2016; 22(1):44-55. PMC: 5414082. DOI: 10.1038/mp.2016.150. View

15.

Sifringer M, Von Haefen C, Krain M, Paeschke N, Bendix I, Buhrer C . Neuroprotective effect of dexmedetomidine on hyperoxia-induced toxicity in the neonatal rat brain. Oxid Med Cell Longev. 2015; 2015:530371. PMC: 4310240. DOI: 10.1155/2015/530371. View

16.

Zhu Y, Zhao P, Sun L, Lu Y, Zhu W, Zhang J . Overexpression of circRNA SNRK targets miR-103-3p to reduce apoptosis and promote cardiac repair through GSK3β/β-catenin pathway in rats with myocardial infarction. Cell Death Discov. 2021; 7(1):84. PMC: 8055694. DOI: 10.1038/s41420-021-00467-3. View

17.

Wu Q, Zheng B, Weng G, Yang H, Ren Y, Weng X . Downregulated NOX4 underlies a novel inhibitory role of microRNA-137 in prostate cancer. J Cell Biochem. 2019; 120(6):10215-10227. DOI: 10.1002/jcb.28306. View

18.

Yang L, Kang K, Lin Y, Wu Y . Up-regulation of miR-137 can inhibit PTN in target manner to regulate PTN/PTPRZ pathway to prevent cognitive dysfunction caused by propofol. Am J Transl Res. 2020; 12(11):7490-7500. PMC: 7724353. View

19.

Bahmad H, Darwish B, Dargham K, Machmouchi R, Dargham B, Osman M . Role of MicroRNAs in Anesthesia-Induced Neurotoxicity in Animal Models and Neuronal Cultures: a Systematic Review. Neurotox Res. 2019; 37(3):479-490. DOI: 10.1007/s12640-019-00135-6. View

20.

Fu C, Dai X, Yang Y, Lin M, Cai Y, Cai S . Dexmedetomidine attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress, mitochondrial dysfunction and apoptosis in rats. Mol Med Rep. 2016; 15(1):131-138. PMC: 5355722. DOI: 10.3892/mmr.2016.6012. View