Neurotoxicity Research

, Volume 35, Issue 1, pp 139–149 | Cite as

Dexmedetomidine Protects Against Chemical Hypoxia-Induced Neurotoxicity in Differentiated PC12 Cells Via Inhibition of NADPH Oxidase 2-Mediated Oxidative Stress

  • Xiao-Hui Chen
  • Dong-Tai Chen
  • Xiong-Mei Huang
  • Yong-Hua Chen
  • Jia-Hao Pan
  • Xiao-Chun Zheng
  • Wei-An Zeng


Dexmedetomidine (Dex) is a widely used sedative in anesthesia and critical care units, and it exhibits neuroprotective activity. However, the precise mechanism of Dex-exerted neuroprotection is not clear. Increased neuronal NADPH oxidase 2 (NOX2) contributes to oxidative stress and neuronal damage in various hypoxia-related neurodegenerative disorders. The present study investigated whether Dex regulated neuronal NOX2 to exert its protective effects under hypoxic conditions. Well-differentiated PC12 cells were exposed to cobalt chloride (CoCl2) to mimic a neuronal model of chemical hypoxia-mediated neurotoxicity. The data showed that Dex pretreatment of PC12 cells significantly suppressed CoCl2-induced neurotoxicity, as evidenced by the enhanced cell viability, restoration of cellular morphology, and reduction in apoptotic cells. Dex improved mitochondrial function and inhibited CoCl2-induced mitochondrial apoptotic pathways. We further demonstrated that Dex attenuated oxidative stress, downregulated NOX2 protein expression and activity, and inhibited intracellular calcium ([Ca2+]i) overload in CoCl2-treated PC12 cells. Moreover, knockdown of the NOX2 gene markedly improved mitochondrial function and attenuated apoptosis under hypoxic conditions. These results demonstrated that the protective effects of Dex against hypoxia-induced neurotoxicity in neural cells were mediated, at least partially, via inhibition of NOX2-mediated oxidative stress.


Dexmedetomidine Hypoxia· NADPH oxidase 2 Oxidative stress PC12 cells 


Funding Information

This study was supported by the Natural Science Foundation of China (NSFC; No. 81571076).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.


  1. Akpinar H, Naziroglu M, Ovey IS, Cig B, Akpinar O (2016) The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: contribution of TRPM2 and TRPV1 channels. Sci Rep 6:37196CrossRefGoogle Scholar
  2. Belarbi K, Cuvelier E, Destee A, Gressier B, Chartier-Harlin MC (2017) NADPH oxidases in Parkinson's disease: a systematic review. Mol Neurodegener 12(1):84CrossRefGoogle Scholar
  3. Brennan AM, Suh SW, Won SJ, Narasimhan P, Kauppinen TM, Lee H, Edling Y, Chan PH, Swanson RA (2009) NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci 12(7):857–863CrossRefGoogle Scholar
  4. Cenini G, Voos W (2016) Role of mitochondrial protein quality control in oxidative stress-induced neurodegenerative diseases. Curr Alzheimer Res 13(2):164–173CrossRefGoogle Scholar
  5. Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H, Maier CM, Narasimhan P, Goeders CE, Chan PH (2011) Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal 14(8):1505–1517CrossRefGoogle Scholar
  6. Chen XH, Zhou X, Yang XY, Zhou ZB, Lu DH, Tang Y, Ling ZM, Zhou LH, Feng X (2016) Propofol protects against H2O2-induced oxidative injury in differentiated PC12 cells via inhibition of ca(2+)-dependent NADPH oxidase. Cell Mol Neurobiol 36(4):541–551CrossRefGoogle Scholar
  7. Correia SC, Carvalho C, Cardoso S, Santos RX, Placido AI, Candeias E, Duarte AI, Moreira PI (2013) Defective HIF signaling pathway and brain response to hypoxia in neurodegenerative diseases: not an "iffy" question! Curr Pharm Des 19(38):6809–6822CrossRefGoogle Scholar
  8. Cui J, Zhao H, Wang C, Sun JJ, Lu K, Ma D (2015) Dexmedetomidine attenuates oxidative stress induced lung alveolar epithelial cell apoptosis in vitro. Oxidative Med Cell Longev 2015:358396CrossRefGoogle Scholar
  9. Degos V, Charpentier TL, Chhor V, Brissaud O, Lebon S, Schwendimann L, Bednareck N, Passemard S, Mantz J, Gressens P (2013) Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to increased astrocyte brain-derived neurotrophic factor expression. Anesthesiology 118(5):1123–1132CrossRefGoogle Scholar
  10. Dupuis L (2014) Mitochondrial quality control in neurodegenerative diseases. Biochimie 100:177–183CrossRefGoogle Scholar
  11. El Jamali A, Valente AJ, Clark RA (2010) Regulation of phagocyte NADPH oxidase by hydrogen peroxide through a ca(2+)/c-Abl signaling pathway. Free Radic Biol Med 48(6):798–810CrossRefGoogle Scholar
  12. Farag E, Argalious M, Abd-Elsayed A, Ebrahim Z, Doyle DJ (2012) The use of Dexmedetomidine in anesthesia and intensive care: a review. Curr Pharm Des 18(38):6257–6265CrossRefGoogle Scholar
  13. Guan D, Su Y, Li Y, Wu C, Meng Y, Peng X, Cui Y (2015) Tetramethylpyrazine inhibits CoCl2 -induced neurotoxicity through enhancement of Nrf2/GCLc/GSH and suppression of HIF1alpha/NOX2/ROS pathways. J Neurochem 134(3):551–565CrossRefGoogle Scholar
  14. Hu X, De Silva TM, Chen J, Faraci FM (2017) Cerebral vascular disease and neurovascular injury in ischemic stroke. Circ Res 120(3):449–471CrossRefGoogle Scholar
  15. Huang L, Li Q, Li H, He Z, Cheng Z, Chen J, Guo L (2009) Inhibition of intracellular Ca2+ release by a rho-kinase inhibitor for the treatment of ischemic damage in primary cultured rat hippocampal neurons. Eur J Pharmacol 602(2–3):238–244CrossRefGoogle Scholar
  16. Infanger DW, Sharma RV, Davisson RL (2006) NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8(9–10):1583–1596CrossRefGoogle Scholar
  17. Jha NK, Jha SK, Sharma R, Kumar D, Ambasta RK, Kumar P (2018) Hypoxia-induced signaling activation in neurodegenerative diseases: targets for new therapeutic strategies. J Alzheimers Dis 62(1):15–38CrossRefGoogle Scholar
  18. Jia J, Ma L, Wu M, Zhang L, Zhang X, Zhai Q, Jiang T, Wang Q, Xiong L (2014) Anandamide protects HT22 cells exposed to hydrogen peroxide by inhibiting CB1 receptor-mediated type 2 NADPH oxidase. Oxidative Med Cell Longev 2014:893516CrossRefGoogle Scholar
  19. Kahles T, Brandes RP (2012) NADPH oxidases as therapeutic targets in ischemic stroke. Cell Mol Life Sci 69(14):2345–2363CrossRefGoogle Scholar
  20. Kim JY, Kim HJ, Kim N, Kwon JH, Park MJ (2017) Effects of radiofrequency field exposure on glutamate-induced oxidative stress in mouse hippocampal HT22 cells. Int J Radiat Biol 93(2):249–256CrossRefGoogle Scholar
  21. Lambert AJ, Brand MD (2009) Reactive oxygen species production by mitochondria. Methods Mol Biol 554:165–181CrossRefGoogle Scholar
  22. Li X, Guo H, Zhao L, Wang B, Liu H, Yue L, Bai H, Jiang H, Gao L, Feng D, Qu Y (2017) Adiponectin attenuates NADPH oxidase-mediated oxidative stress and neuronal damage induced by cerebral ischemia-reperfusion injury. Biochim Biophys Acta 1863(12):3265–3276CrossRefGoogle Scholar
  23. Liu X, Zhu XY, Chen M, Ge QM, Shen Y, Pan SM (2016) Resveratrol protects PC12 cells against OGD/R-induced apoptosis via the mitochondrial-mediated signaling pathway. Acta Bioch Bioph Sin 48(4):342–353CrossRefGoogle Scholar
  24. Lu Q, Wainwright MS, Harris VA, Aggarwal S, Hou Y, Rau T, Poulsen DJ, Black SM (2012) Increased NADPH oxidase-derived superoxide is involved in the neuronal cell death induced by hypoxia-ischemia in neonatal hippocampal slice cultures. Free Radic Biol Med 53(5):1139–1151CrossRefGoogle Scholar
  25. Luo H, Huang J, Liao WG, Huang QY, Gao YQ (2011) The antioxidant effects of garlic saponins protect PC12 cells from hypoxia-induced damage. Br J Nutr 105(8):1164–1172CrossRefGoogle Scholar
  26. Ma MW, Wang J, Zhang Q, Wang R, Dhandapani KM, Vadlamudi RK, Brann DW (2017) NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 12(1):7CrossRefGoogle Scholar
  27. Martin TFJ, Grishanin RN (2003) PC12 cells as a model for studies of regulated secretion in neuronal and endocrine cells. Method Cell Biol 71:267–286CrossRefGoogle Scholar
  28. Pan W, Lin L, Zhang N, Yuan F, Hua X, Wang Y, Mo L (2015) Neuroprotective effects of Dexmedetomidine against hypoxia-induced nervous system injury are related to inhibition of NF-κB/COX-2 pathways. Cell Mol Neurobiol 36(7):1179–1188CrossRefGoogle Scholar
  29. Pan XQ, Yan DD, Wang D, Wu X, Zhao WY, Lu Q, Yan H (2017) Mitochondrion-mediated apoptosis induced by acrylamide is regulated by a balance between Nrf2 antioxidant and MAPK signaling pathways in PC12 cells. Mol Neurobiol 54(6):4781–4794CrossRefGoogle Scholar
  30. Ren X, Ma H, Zuo Z (2016) Dexmedetomidine Postconditioning reduces brain injury after brain hypoxia-ischemia in neonatal rats. J Neuroimmune Pharmacol 11(2):238–247CrossRefGoogle Scholar
  31. Shuangyan W, Ruowu S, Hongli N, Bei Z, Yong S (2012) Protective effects of Rg2 on hypoxia-induced neuronal damage in hippocampal neurons. Artif Cells Blood Substit Immobil Biotechnol 40(1–2):142–145CrossRefGoogle Scholar
  32. Stoetzer C, Reuter S, Doll T, Foadi N, Wegner F, Leffler A (2016) Inhibition of the cardiac Na(+) channel alpha-subunit Nav1.5 by propofol and dexmedetomidine. Naunyn Schmiedeberg's Arch Pharmacol 389(3):315–325CrossRefGoogle Scholar
  33. Takizuka A, Minami K, Uezono Y, Horishita T, Yokoyama T, Shiraishi M, Sakurai T, Shigematsu A, Ueta Y (2007) Dexmedetomidine inhibits muscarinic type 3 receptors expressed in Xenopus oocytes and muscarine-induced intracellular Ca2+ elevation in cultured rat dorsal root ganglia cells. Naunyn Schmiedeberg's Arch Pharmacol 375(5):293–301CrossRefGoogle Scholar
  34. Taylor SC, Posch A (2014) The design of a quantitative western blot experiment. Biomed Res Int 2014:361590CrossRefGoogle Scholar
  35. Thiraphatthanavong P, Wattanathorn J, Muchimapura S, Thukham-Mee W, Lertrat K, Suriharn B (2014) The combined extract of purple waxy corn and ginger prevents cataractogenesis and retinopathy in streptozotocin-diabetic rats. Oxidative Med Cell Longev 2014:789406CrossRefGoogle Scholar
  36. Venn RM, Karol MD, Grounds RM (2002) Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive caret. Br J Anaesth 88(5):669–675CrossRefGoogle Scholar
  37. Wu GJ, Chen JT, Tsai HC, Chen TL, Liu SH, Chen RM (2016) Protection of dexmedetomidine against ischemia/reperfusion-induced apoptotic insults to neuronal cells occurs via an intrinsic mitochondria-dependent pathway. J Cell Biochem 118(9):2635–264Google Scholar
  38. Xu Y, Kabba JA, Ruan W, Wang Y, Zhao S, Song X, Zhang L, Li J, Pang T (2018) The PGC-1alpha activator ZLN005 ameliorates ischemia-induced neuronal injury in vitro and in vivo. Cell Mol Neurobiol 38(4):929–939CrossRefGoogle Scholar
  39. Yuan X, Guo X, Deng Y, Zhu D, Shang J, Liu H (2015) Chronic intermittent hypoxia-induced neuronal apoptosis in the hippocampus is attenuated by telmisartan through suppression of iNOS/NO and inhibition of lipid peroxidation and inflammatory responses. Brain Res 1596:48–57CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Xiao-Hui Chen
    • 1
    • 2
  • Dong-Tai Chen
    • 1
  • Xiong-Mei Huang
    • 3
  • Yong-Hua Chen
    • 4
  • Jia-Hao Pan
    • 1
  • Xiao-Chun Zheng
    • 2
  • Wei-An Zeng
    • 1
  1. 1.Department of AnesthesiologySun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
  2. 2.Department of AnesthesiologyFujian Provincial Clinical Medical College, Fujian Medical University, Fujian Provincial HospitalFuzhouChina
  3. 3.Department of Burn and Plastic SurgeryFujian Provincial Clinical Medical College, Fujian Medical University, Fujian Provincial HospitalFuzhouChina
  4. 4.Department of AnesthesiologyPeking University Shenzhen HospitalShenzhenChina

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