Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Neuroprotection of Dexmedetomidine against Cerebral Ischemia-Reperfusion Injury in Rats: Involved in Inhibition of NF-κB and Inflammation Response

  • Wang, Lijun (Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Liu, Haiyan (Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Zhang, Ligong (Department of Anesthesia, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Wang, Gongming (Department of Anesthesia, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Zhang, Mengyuan (Department of Anesthesia, Shandong Provincial Hospital Affiliated to Shandong University) ;
  • Yu, Yonghui (Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University)
  • Received : 2015.11.09
  • Accepted : 2016.09.21
  • Published : 2017.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

Dexmedetomidine is an ${\alpha}2$-adrenergic receptor agonist that exhibits a protective effect on ischemia-reperfusion injury of the heart, kidney, and other organs. In the present study, we examined the neuroprotective action and potential mechanisms of dexmedetomidine against ischemia-reperfusion induced cerebral injury. Transient focal cerebral ischemia-reperfusion injury was induced in Sprague-Dawley rats by middle cerebral artery occlusion. After the ischemic insult, animals then received intravenous dexmedetomidine of $1{\mu}g/kg$ load dose, followed by $0.05{\mu}g/kg/min$ infusion for 2 h. After 24 h of reperfusion, neurological function, brain edema, and the morphology of the hippocampal CA1 region were evaluated. The levels and mRNA expressions of interleukin-$1{\beta}$, interleukin-6 and tumor nevrosis factor-${\alpha}$ as well as the protein expression of inducible nitric oxide synthase, cyclooxygenase-2, nuclear factor-${\kappa}Bp65$, inhibitor of ${\kappa}B{\alpha}$ and phosphorylated of ${\kappa}B{\alpha}$ in hippocampus were assessed. We found that dexmedetomidine reduced focal cerebral ischemia-reperfusion injury in rats by inhibiting the expression and release of inflammatory cytokines and mediators. Inhibition of the nuclear factor-${\kappa}B$ pathway may be a mechanism underlying the neuroprotective action of dexmedetomidine against focal cerebral I/R injury.

Keywords

References

  1. Baldwin, A. S., Jr. (1996) The NF-${\kappa}B$ and $I{\kappa}B$ proteins: new discoveries and insights. Annu. Rev. Immunol. 14, 649-683. https://doi.org/10.1146/annurev.immunol.14.1.649
  2. Basu, A., Lazovic, J., Krady, J. K., Mauger, D. T., Rothstein, R. P., Smith, M. B. and Levison, S. W. (2005) Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury. J. Cereb. Blood Flow Metab. 25, 17-29. https://doi.org/10.1038/sj.jcbfm.9600002
  3. Berti, R., Williams, A. J., Moffett, J. R., Hale, S. L., Velarde, L. C., Elliott, P. J., Yao, C., Dave, J. R. and Tortella, F. C. (2002) Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia-reperfusion brain injury. J. Cereb. Blood Flow Metab. 22, 1068-1079. https://doi.org/10.1097/00004647-200209000-00004
  4. Boersma, M. C. and Meffert, M. K. (2008) Novel roles for the NF-${\kappa}B$ signaling pathway in regulating neuronal function. Sci. Signal. 1, pe7
  5. Borlongan, C. V., Hida, H. and Nishino, H. (1998) Early assessment of motor dysfunctions aids in successful occlusion of the middle cerebral artery. Neuroreport. 9, 3615-3621. https://doi.org/10.1097/00001756-199811160-00012
  6. Culmsee, C. and Krieqlstein, J. (2007) Ischaemic brain damage after stroke: new insights into efficient therapeutic strategies. International Symposium on Neurodegeneration and Neuroprotection. EMBO Rep. 8, 129-133. https://doi.org/10.1038/sj.embor.7400892
  7. Cui, D. R., Wang, L., Jiang, W., Qi, A. H., Zhou, Q. H. and Zhang, X. L. (2013) Propofol prevents cerebral ischemia-triggered autophagy activation and cell death in the rat hippocampus through the NF-${\kappa}B$/p53 signaling pathway. Neuroscience 246, 117-132. https://doi.org/10.1016/j.neuroscience.2013.04.054
  8. Derugin, N., Wendland, M., Muramatsu, K., Roberts, T. P., Gregory, G., Ferriero, D. M. and Vexler, Z. S. (2000) Evolution of brain injury after transient middle cerebral artery occlusion in neonatal rats. Stroke 31, 1752-1761. https://doi.org/10.1161/01.STR.31.7.1752
  9. Dimagl, U., ladecola, C. and Moskowitz, M. A. (1999) Pathobiology of ischaemic stroke : an integrated view. Trends Neurosci. 22, 391-397. https://doi.org/10.1016/S0166-2236(99)01401-0
  10. Ferriero, D. M., Holtzman, D. M., Black, S. M. and Sheldon, R. A. (1996) Neonatal mice lacking neuronal nitric oxide synthase are less vulnerable to hypoxic-ischemic injury. Neurobiol. Dis. 3, 64-71. https://doi.org/10.1006/nbdi.1996.0006
  11. Fujita, M., Tsuruta, R., Kaneko, T., Otsuka, Y., Kutsuna, S., Izumi, T., Aoki, T., Shitara, M., Kasaoka, S., Maruyama, I., Yuasa, M. and Maekawa, T. (2010) Hyperoxia suppresses excessive superoxide anion radical generation in blood, oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion rats: laboratory study. Shock 34, 299-305. https://doi.org/10.1097/SHK.0b013e3181ceeeec
  12. Guo, Y., Xu, X., Li, Q., Li, Z. and Du, F. (2010) Anti-inflammation effects of picroside 2 in cerebral ischemic injury rats. Behav. Brain Funct. 6, 43. https://doi.org/10.1186/1744-9081-6-43
  13. Hoffman, W. E., Kochs, E., Werner, C., Thomas, C. and Albrecht, R. F. (1991) Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat: Reversal by the ${\alpha}2$-adrenergic antagonist atipamezole. Anesthesiology 75, 328-332. https://doi.org/10.1097/00000542-199108000-00022
  14. Hseu, Y. C., Wu, F. Y., Wu, J. J., Chen, J. Y., Chang, W. H., Lu, F. J., Lai, Y. C. and Yang, H. L. (2005) Anti-inflammatory potential of Antrodia Camphorata through inhibition of iNOS, COX-2 and cytokines via the NF-${\kappa}B$ pathway. Int. Immunopharmacol. 5, 1914-1925. https://doi.org/10.1016/j.intimp.2005.06.013
  15. Iadecola, C., Zhang, F., Casey, R., Nagayama, M. and Ross, M. E. (1997) Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J. Neurosci. 17, 9157-9164. https://doi.org/10.1523/JNEUROSCI.17-23-09157.1997
  16. Jiang, Q., Xia, Y. Y., He, J. M., Guo, M. L. and Li, R. P. (2014) Total bakkenolides protects neurons against cerebral ischemic injury through inhibition of nuclear factor-${\kappa}B$ activation. CNS Neurol. Disord. Drug Targets 13, 874-884. https://doi.org/10.2174/18715273113129990104
  17. Kamibayashi, T. and Maze, M. (2000) Clinical uses of ${\alpha}2$-adrenergic agonists. Anesthesiology 93, 1345-1349. https://doi.org/10.1097/00000542-200011000-00030
  18. Kim, D. H., Kim, S., Jung, W. Y., Park, S. J., Park, D. H., Kim, J. M., Cheong, J. H. and Ryu, J. H. (2009) The neuroprotective effects of the seeds of Cassia obtusifolia on transient cerebral global ischemia in mice. Food Chem. Toxicol. 47, 1473-1479. https://doi.org/10.1016/j.fct.2009.03.028
  19. Kocoglu, H., Ozturk, H., Ozturk, H., Yilmaz, F. and Gulcu, N. (2009) Effect of dexmedetomidine on ischemia-reperfusion injury in rat kidney: A histopathologic study. Ren. Fail. 31, 70-74. https://doi.org/10.1080/08860220802546487
  20. Koistinaho, J., Koponen, S. and Chan, P. H. (1999) Expression of cyclooxygenase-2 mRNA after global ischemia is regulated by AMPA receptors and glucocorticoids. Stroke 30, 1900-1905; discussion 1905-1906. https://doi.org/10.1161/01.STR.30.9.1900
  21. Kuhmonen, J., Haapalinna, A. and Sivenius, J. (2001) Effects of dexmedetomidine after transient and permanent occlusion of the middle cerebral artery in the rat. J. Neural Transm. (Vienna) 108, 261-271. https://doi.org/10.1007/s007020170071
  22. Laudenbach, V., Mantz, J., Lagercrantz, H., Desmonts, J. M., Evrard, P. and Gressens, P. (2002) Effects of ${\alpha}2$-adrenoceptor agonists on perinatal excitotoxic brain injury: comparison of clonidine and dexmedetomidine. Anesthesiology 96, 134-141. https://doi.org/10.1097/00000542-200201000-00026
  23. Lee, J. M., Grabb, M. C., Zipfel, G. J. and Choi, D. W. (2000) Brain tissue responses to ischemia. J. Clin. Invest. 106, 723-731. https://doi.org/10.1172/JCI11003
  24. Longa, E. Z., Weinstein, P. R., Carlson, S. and Cummins, R. (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84-91. https://doi.org/10.1161/01.STR.20.1.84
  25. Lou, H. Y., Wei, X. B., Zhang, B., Sun, X. and Zhang, X. M. (2007) Hydroxyethylpuerarin attenuates focal cerebral ischemia-reperfusion injury in rats by decreasing TNF-${\alpha}$ expression and NF${\kappa}B$ activity. Yao Xue Xue Bao 42, 710-715.
  26. Min, K. J., Cho, K. H. and Kwon, T. K. (2012) The effect of oxidized low density lipoprotein (oxLDL)-induced heme oxygenase-1 on LPS-induced inflammation in RAW 264.7 macrophage cells. Cell. Signal. 24, 1215-1221. https://doi.org/10.1016/j.cellsig.2012.02.001
  27. Okada, H., Kurita, T., Mochizuki, T., Morita, K. and Sato, S. (2007) The cardioprotective effect of dexmedetomidine on global ischaemia in isolated rat hearts. Resuscitation 74, 538-545. https://doi.org/10.1016/j.resuscitation.2007.01.032
  28. Qiao, H., Zhang, X., Zhu, C., Dong, L., Wang, L., Zhang, X., Xing, Y., Wang, C., Ji, Y. and Cao, X. (2012) Luteolin downregulates TLR4, TLR5, NF-${\kappa}B$ and p-p38MAPK expression, upregulates the p-ERK expression, and protects rat brains against focal ischemia. Brain Res. 1448, 71-81. https://doi.org/10.1016/j.brainres.2012.02.003
  29. Ritter, L. S., Orozco, J. A., Coull, B. M., McDonagh, P. F. and Rosenblum, W. I. (2000) Leukocyte accumulation and hemodynamic changes in the cerebral microcirculation during early reperfusion after stroke. Stroke 31, 1153-1161. https://doi.org/10.1161/01.STR.31.5.1153
  30. Wang, C., Liu, J. L., Sang, H. F., Lu, Y., Dong, H. L. and Xiong, L. Z. (2008) Therapeutic time window of flurbiprofen axetil's neuroprotective effect in a rat model of transient focal cerebral ischemia. Chin. Med. J. 121, 2572-2577.
  31. Xie, C., Kang, J., Ferguson, M. E., Nagarajan, S., Badger, T. M. and Wu, X. (2011) Blueberries reduce pro-inflammatory cytokine TNF-${\alpha}$ and IL-6 production in mouse macrophages by inhibiting NF-${\kappa}B$ activation and the MAPK pathway. Mol Nutr. Food Res. 55, 1587-1591. https://doi.org/10.1002/mnfr.201100344
  32. Yasuda, Y., Shimoda, T., Uno, K., Tateishi, N., Furuya, S., Tsuchihashi, Y. Kawai, Y., Naruse, S. and Fujita, S. (2011) Temporal and sequential changes of glial cells and cytokine expression during neuronal degeneration after transient global ischemia in rats. J. Neuroinflammation. 8, 70. https://doi.org/10.1186/1742-2094-8-70
  33. Zhang, J., Zhen, Y. F., Pu-Bu-Ci-Ren, Song, L. G., Kong, W. N., Shao, T. M., Li, X. And Chai, X. Q. (2013) Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus. Behav. Brain Res. 244, 70-81. https://doi.org/10.1016/j.bbr.2013.01.037
  34. Zhang, X. Y., Liu, Z. M., Wen, S. H., Li, Y. S., Li, Y., Yao, X., Huang, W. Q. and Liu, K. X. (2012) Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats. Anesthesiology 116, 1035-1046. https://doi.org/10.1097/ALN.0b013e3182503964
  35. Zhao, P., Ji, G., Xue, H., Yu, W., Zhao, X., Ding, M., Yang, Y. and Zuo, Z. (2014) Isoflurane postconditioning improved long-term neurological outcome possibly via inhibiting the mitochondrial permeability transition pore in neonatal rats after brain hypoxia-ischemia. Neuroscience 280, 193-203. https://doi.org/10.1016/j.neuroscience.2014.09.006

Cited by

  1. Participation of NO-synthase in Control of Nitric Oxide Level in Rat Hippocampus after Modelling of Ischaemic and Haemorrhagic Insult vol.20, pp.2050-2966, 2017, https://doi.org/10.3897/biodiscovery.20.e14810
  2. Dexmedetomidine protects mice against myocardium ischaemic/reperfusion injury by activating an AMPK/PI3K/Akt/eNOS pathway vol.44, pp.9, 2017, https://doi.org/10.1111/1440-1681.12791
  3. Does Dexmedetomidine Ameliorate Postoperative Cognitive Dysfunction? A Brief Review of the Recent Literature vol.18, pp.10, 2018, https://doi.org/10.1007/s11910-018-0873-z
  4. Genome-wide transcriptome analysis using RNA-Seq reveals a large number of differentially expressed genes in a transient MCAO rat model vol.19, pp.1, 2018, https://doi.org/10.1186/s12864-018-5039-5
  5. Dexmedetomidine inhibits inflammatory reaction in the hippocampus of septic rats by suppressing NF-κB pathway vol.13, pp.5, 2018, https://doi.org/10.1371/journal.pone.0196897
  6. Dexmedetomidine attenuates traumatic brain injury: action pathway and mechanisms vol.13, pp.5, 2018, https://doi.org/10.4103/1673-5374.232529
  7. Hyperoside protects against cerebral ischemia-reperfusion injury by alleviating oxidative stress, inflammation and apoptosis in rats vol.33, pp.1, 2017, https://doi.org/10.1080/13102818.2019.1620633
  8. miR-223-3p/TIAL1 interaction is involved in the mechanisms associated with the neuroprotective effects of dexmedetomidine on hippocampal neuronal cells in vitro vol.19, pp.2, 2017, https://doi.org/10.3892/mmr.2018.9742
  9. Neuroprotective effect of chlorogenic acid in global cerebral ischemia-reperfusion rat model vol.392, pp.10, 2017, https://doi.org/10.1007/s00210-019-01670-x
  10. Dexmedetomidine inhibits neuronal apoptosis by inducing Sigma-1 receptor signaling in cerebral ischemia-reperfusion injury vol.11, pp.21, 2017, https://doi.org/10.18632/aging.102404
  11. Dexmedetomidine suppresses sevoflurane anesthesia-induced neuroinflammation through activation of the PI3K/Akt/mTOR pathway vol.19, pp.1, 2017, https://doi.org/10.1186/s12871-019-0808-5
  12. Mechanisms of Dexmedetomidine in Neuropathic Pain vol.14, pp.None, 2017, https://doi.org/10.3389/fnins.2020.00330
  13. Dexmedetomidine inhibits inflammatory response and autophagy through the circLrp1b/miR-27a-3p/Dram2 pathway in a rat model of traumatic brain injury vol.12, pp.21, 2020, https://doi.org/10.18632/aging.103975
  14. Postoperative delirium after long-term general anesthesia in elderly patients, how to reduce it? : Protocol of a double-blinded, randomized, placebo-controlled trial vol.100, pp.22, 2017, https://doi.org/10.1097/md.0000000000025885
  15. Galangin attenuated cerebral ischemia-reperfusion injury by inhibition of ferroptosis through activating the SLC7A11/GPX4 axis in gerbils vol.264, pp.None, 2017, https://doi.org/10.1016/j.lfs.2020.118660
  16. DL0410 Alleviates Memory Impairment in D-Galactose-Induced Aging Rats by Suppressing Neuroinflammation via the TLR4/MyD88/NF-κB Pathway vol.2021, pp.None, 2017, https://doi.org/10.1155/2021/6521146
  17. Hypoxia-Inducible Factor (HIF) in Ischemic Stroke and Neurodegenerative Disease vol.9, pp.None, 2017, https://doi.org/10.3389/fcell.2021.703084
  18. Dexmedetomidine‐up‐regulated microRNA‐381 exerts anti‐inflammatory effects in rats with cerebral ischaemic injury via the transcriptional factor IRF4 vol.25, pp.4, 2021, https://doi.org/10.1111/jcmm.16153
  19. Dexmedetomidine Resists Intestinal Ischemia-Reperfusion Injury by Inhibiting TLR4/MyD88/NF-κB Signaling vol.260, pp.None, 2017, https://doi.org/10.1016/j.jss.2020.11.041
  20. Why do We Use the Concepts of Adult Anesthesia Pharmacology in Developing Brains? Will It Have an Impact on Outcomes? Challenges in Neuromonitoring and Pharmacology in Pediatric Anesthesia vol.10, pp.10, 2017, https://doi.org/10.3390/jcm10102175
  21. The Current Role of Dexmedetomidine as Neuroprotective Agent: An Updated Review vol.11, pp.7, 2021, https://doi.org/10.3390/brainsci11070846
  22. Novel Stachydrine-Leonurine Conjugate SL06 as a Potent Neuroprotective Agent for Cerebral Ischemic Stroke vol.12, pp.13, 2021, https://doi.org/10.1021/acschemneuro.1c00200
  23. Protective effects of dexmedetomidine on cerebral ischemia/reperfusion injury via the microRNA-214/ROCK1/NF-κB axis vol.21, pp.1, 2021, https://doi.org/10.1186/s12871-021-01423-5