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Cellular and Molecular Neurobiology

, Volume 36, Issue 7, pp 1179–1188 | Cite as

Neuroprotective Effects of Dexmedetomidine Against Hypoxia-Induced Nervous System Injury are Related to Inhibition of NF-κB/COX-2 Pathways

  • Wanying Pan
  • Lin Lin
  • Nan Zhang
  • Fuli Yuan
  • Xiaoxiao Hua
  • Yueting Wang
  • Liqiu MoEmail author
Original Research

Abstract

Dexmedetomidine has been reported to provide neuroprotection against hypoxia-induced damage. However, the underlying mechanisms remain unclear. We examined whether dexmedetomidine’s neuroprotective effects were mediated by the NF-κB/COX-2 pathways. Adult male C57BL/6 mice were subjected to a 30-min hypoxic treatment followed by recovery to normal conditions. They received dexmedetomidine (16 or 160 μg/kg) or 25 mg/kg atipamezole, an α2-adrenoreceptor antagonist, intraperitoneally before exposure to hypoxia. The whole brain was harvested 6, 18, or 36 h after the hypoxia to determine the histopathological outcome and cleaved caspase-3, Bax/Bcl, NF-κB, and COX-2 levels. Hypoxia treatment induced significant neurotoxicity, including destruction of the tissue structure and upregulation of the protein levels of caspase-3, the ratio of Bax/Bcl-2, NF-κB, and COX-2. Dexmedetomidine pretreatment effectively improved histological outcome and restored levels of caspase-3, the Bax/Bcl-2 ratio, NF-κB, and COX-2. Atipamezole reversed the neuroprotection induced by dexmedetomidine. Neuroprotection was achieved by PDTC and NS-398, inhibitors of NF-κB and COX-2, respectively. Dexmedetomidine use before hypoxia provides neuroprotection. Inhibition of NF-κB/COX-2 pathways activation may contribute to the neuroprotection of dexmedetomidine.

Keywords

Dexmedetomidine Hypoxia Neuroprotection NF-κB COX-2 

Notes

Acknowledgments

Supported by grant 2012B031800289 from the science and technology plan projects of Guangdong Province (to Dr. L-Q Mo).

Compliance with Ethical Standards

Conflict of Interest

There is no conflict of interests regarding the publication of this paper.

References

  1. Baldwin AS Jr (2001) Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest 107(1):3–6CrossRefPubMedPubMedCentralGoogle Scholar
  2. Chang YC, Huang CC (2006) Perinatal brain injury and regulation of transcription. Curr Opin Neurol 19(2):141–147CrossRefPubMedGoogle Scholar
  3. Chen Y, Miao L, Yao Y, Wu W, Wu X, Gong C, Qiu L, Chen J (2015) Dexmedetomidine ameliorate CLP-induced rat intestinal injury via inhibition of inflammation. Mediat Inflamm 2015:918361. doi: 10.1155/2015/918361 Google Scholar
  4. Chrysostomou C, Schmitt CG (2008) Dexmedetomidine: sedation, analgesia and beyond. Expert Opin Drug Metab Toxicol 4(5):619–627. doi: 10.1517/17425255.4.5.619 CrossRefPubMedGoogle Scholar
  5. Dahmani S, Paris A, Jannier V, Hein L, Rouelle D, Scholz J, Gressens P, Mantz J (2008) Dexmedetomidine increases hippocampal phosphorylated extracellular signal-regulated protein kinase 1 and 2 content by an alpha 2-adrenoceptor-independent mechanism: evidence for the involvement of imidazoline I1 receptors. Anesthesiology 108(3):457–466. doi: 10.1097/ALN.0b013e318164ca81 CrossRefPubMedGoogle Scholar
  6. 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):1123–1132. doi: 10.1097/ALN.0b013e318286cf36 CrossRefPubMedGoogle Scholar
  7. Deng Y, Lu J, Sivakumar V, Ling EA, Kaur C (2008) Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats. Brain Pathol 18(3):387–400. doi: 10.1111/j.1750-3639.2008.00138.x CrossRefPubMedGoogle Scholar
  8. Drouin-Ouellet J, Cicchetti F (2012) Inflammation and neurodegeneration: the story ‘retolled’. Trends Pharmacol Sci 33(10):542–551. doi: 10.1016/j.tips.2012.07.002 CrossRefPubMedGoogle Scholar
  9. Du T, Li B, Liu S, Zang P, Prevot V, Hertz L, Peng L (2009) ERK phosphorylation in intact, adult brain by alpha(2)-adrenergic transactivation of EGF receptors. Neurochem Int 55(7):593–600. doi: 10.1016/j.neuint.2009.05.016 CrossRefPubMedGoogle Scholar
  10. Hewett SJ, Bell SC, Hewett JA (2006) Contributions of cyclooxygenase-2 to neuroplasticity and neuropathology of the central nervous system. Pharmacol Ther 112(2):335–357CrossRefPubMedGoogle Scholar
  11. Ibacache M, Sanchez G, Pedrozo Z, Galvez F, Humeres C, Echevarria G, Duaso J, Hassi M, Garcia L, Díaz-Araya G, Lavandero S (2012) Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart. Biochim Biophys Acta 1822(4):537–545. doi: 10.1016/j.bbadis.2011.12.013 CrossRefPubMedGoogle Scholar
  12. Janke EL, Samra S (2006) Dexmedetomidine and neuroprotection. Semin Anesth Perioper Med Pain 25(2):71–76. doi: 10.1053/j.sane.2006.02.002 CrossRefGoogle Scholar
  13. Kim CH, Kim JH, Lee J, Ahn YS (2003) Zinc-induced NF-kappaB inhibition can be modulated by changes in the intracellular metallothionein level. Toxicol Appl Pharmacol 190(2):189–196CrossRefPubMedGoogle Scholar
  14. Li S, Yang Y, Yu C, Yao Y, Wu Y, Qian L, Cheung CW (2015) Dexmedetomidine analgesia effects in patients undergoing dental implant surgery and its impact on postoperative inflammatory and oxidative stress. Oxid Med Cell Longev 2015:186736. doi: 10.1155/2015/186736 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Liao Z, Cao D, Han X, Liu C, Peng J, Zuo Z, Wang F, Li Y (2014) Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats. Brain Res Bull 107:69–78. doi: 10.1016/j.brainresbull.2014.07.001 CrossRefPubMedGoogle Scholar
  16. Lin HY, Tang HY, Davis FB, Davis PJ (2011) Resveratrol and apoptosis. Ann N Y Acad Sci 1215:79–88. doi: 10.1111/j.1749-6632.2010.05846.x CrossRefPubMedGoogle Scholar
  17. Ma D, Hossain M, Rajakumaraswamy N, Arshad M, Sanders RD, Franks NP, Maze M (2004) Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype. Eur J Pharmacol 502(1–2):87–97CrossRefPubMedGoogle Scholar
  18. Maier C, Steinberg GK, Sun GH, Zhi GT, Maze M (1993) Neuroprotection by the alpha 2-adrenoreceptor agonist dexmedetomidine in a focal model of cerebral ischemia. Anesthesiology 79(2):306–312CrossRefPubMedGoogle Scholar
  19. Mattson MP, Camandola S (2001) NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107(3):247–254CrossRefPubMedPubMedCentralGoogle Scholar
  20. Minghetti L (2007) Role of COX-2 in inflammatory and degenerative brain diseases. Subcell Biochem 42:127–141CrossRefPubMedGoogle Scholar
  21. Nagayama M, Niwa K, Nagayama T, Ross ME, Iadecola C (1999) The cyclooxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury in wild-type mice but not in mice with deletion of the inducible nitric oxide synthase gene. J Cereb Blood Flow Metab 19(11):1213–1219CrossRefPubMedGoogle Scholar
  22. Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, Weih F, Frank N, Schwaninger M, Koistinaho J (2004) Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke 35(4):987–991CrossRefPubMedGoogle Scholar
  23. Pan WY, Hua XX, Wang YT, Guo RX, Chen JF, Mo LQ (in press) Dosage response of dexmedetomidine-induced resistance to hypoxia in mice. molecular medicine reports. In pressGoogle Scholar
  24. Paris A, Mantz J, Tonner PH, Hein L, Brede M, Gressens P (2006) The effects of dexmedetomidine on perinatal excitotoxic brain injury are mediated by the alpha2A-adrenoceptor subtype. Anesth Analg 102(2):456–461CrossRefPubMedGoogle Scholar
  25. Ridder DA, Schwaninger M (2009) NF-kappaB signaling in cerebral ischemia. Neuroscience 158(3):995–1006. doi: 10.1016/j.neuroscience.2008.07.007 CrossRefPubMedGoogle Scholar
  26. Rupalla K, Allegrini PR, Sauer D, Wiessner C (1998) Time course of microglia activation and apoptosis in various brain regions after permanent focal cerebral ischemia in mice. Acta Neuropathol 96(2):172–178CrossRefPubMedGoogle Scholar
  27. Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M (1999) NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med 5(5):554–559CrossRefPubMedGoogle Scholar
  28. Shen N, Mo LQ, Hu F, Chen PX, Guo RX, Feng JQ (2014) A novel role of spinal astrocytic connexin 43: mediating morphine antinociceptive tolerance by activation of NMDA receptors and inhibition of glutamate transporter-1 in rats. CNS Neurosci Ther 20(8):728–736. doi: 10.1111/cns.12244 CrossRefPubMedGoogle Scholar
  29. Sulemanji DS, Dönmez A, Aldemir D, Sezgin A, Türkoglu S (2007) Dexmedetomidine during coronary artery bypass grafting surgery: is it neuroprotective?–A preliminary study. Acta Anaesthesiol Scand 51(8):1093–1098CrossRefPubMedGoogle Scholar
  30. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS (2001) Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 480–481:243–268CrossRefPubMedGoogle Scholar
  31. Tosun Z, Baktir M, Kahraman HC, Baskol G, Guler G, Boyaci A (2013) Does dexmedetomidine provide cardioprotection in coronary artery bypass grafting with cardiopulmonary bypass? A pilot study. J Cardiothorac Vasc Anesth 27(4):710–715. doi: 10.1053/j.jvca.2012.12.013 CrossRefPubMedGoogle Scholar
  32. Virtanen R, Savola JM, Saano V (1989) Highly selective and specific antagonism of central and peripheral alpha 2-adrenoceptors by atipamezole. Arch Int Pharmacodyn Ther 297:190–204PubMedGoogle Scholar
  33. Ye HH, Hua R, Yu L, Wu KJ, Fei SJ, Qin X, Song Y, Cao JL, Zhang YM (2013) Abnormal expression of Toll-like receptor 4 is associated with susceptibility to ethanol-induced gastric mucosal injury in mice. Dig Dis Sci 58(10):2826–2839. doi: 10.1007/s10620-013-2727-5 CrossRefPubMedGoogle Scholar
  34. Zhang XY, Liu ZM, Wen SH, Li YS, Li Y, Yao X, Huang WQ, Liu KX (2012) Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats. Anesthesiology 116(5):1035–1046. doi: 10.1097/ALN.0b013e3182503964 CrossRefPubMedGoogle Scholar
  35. Zhang Q, Yuan L, Liu D, Wang J, Wang S, Zhang Q, Gong Y, Liu H, Hao A, Wang Z (2014) Hydrogen sulfide attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation. Pharmacol Res 84:32–44. doi: 10.1016/j.phrs.2014.04.009 CrossRefPubMedGoogle Scholar
  36. Zhu YM, Wang CC, Chen L, Qian LB, Ma LL, Yu J, Zhu MH, Wen CY, Yu LN, Yan M (2013) Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats. Brain Res 1494:1–8. doi: 10.1016/j.brainres.2012.11.047 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Wanying Pan
    • 1
  • Lin Lin
    • 1
  • Nan Zhang
    • 1
  • Fuli Yuan
    • 1
  • Xiaoxiao Hua
    • 1
  • Yueting Wang
    • 1
  • Liqiu Mo
    • 1
    Email author
  1. 1.Department of Anesthesiology, The First Affiliated HospitalSun Yat-sen UniversityGuangzhouChina

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