Neuroprotective role of the Alpha 2-Adrenergic Agonist Dexmedetomidine in Ischemic Cerebrovascular Disease

Abstract

Abstract: Ischemic cerebrovascular disease is a common and frequently encountered disease with high disability and mortality rates, and has severe effects on human’s health and quality of life. Cerebral hypoxic ischemia leads to an increase in the number of damaged or dead neurons. Recent studies have provided considerable evidence that alpha 2-adrenergic agonists can protect the brain neuron from cerebral ischemia/reperfusion injury. However, the exact mechanisms of this protection remain unknown. Activation of the alpha 2-adrenergic receptor may be involved. Dexmedetomidine is a highly selective agonist of the alpha 2-adrenergic receptors with neuroprotective effects. This article reviews the pathophysiological process of ischemic cerebrovascular disease, the molecular pharmacology and the neuroprotective mechanisms of dexmedetomidine.

Key words: alpha 2-adrenergic agonists, dexmedetomidine, ischemic cerebrovascular disease, neuroprotection

CLC Number:

R964

HU Min, HE Zhi. Neuroprotective role of the Alpha 2-Adrenergic Agonist Dexmedetomidine in Ischemic Cerebrovascular Disease[J]. ACTA NEUROPHARMACOLOGICA, 2011, 1(5): 49-55.

References

1. Guo Min-fang, Yu Jie-zhong, Ma Cun-gen. Mechanisms related to neuron injury and death in cerebral hypoxic ischaemia[J]. Folia Neuropathol, 2011, 49(2): 78-87.

2. Kamibayashi Takahiko, Maze Mervyn. Clinical uses of α2-adrenergic agonists[J]. Anesthesiol, 2000, 93(5): 1345-1349.

3. Ilfeld Brian M, Morey Timothy E, Thannikary Lisa J, et al. Clonidine added to a continuous interscalene ropivacaine perineural infusion to improve postoperative analgesia: a randomized, double-blind, controlled study[J]. Anesth Analg, 2005, 100(4): 1172-1178.

4. Ma Daqing, Rajakumaraswamy Nishanthan, Maze Mervyn. α2-Adrenoceptor agonists: shedding light on neuroprotection?[J]. Br Med Bull, 2005, 71(1): 77-92.

5. Bell Marshall T, Puskas Ferenc, Smith Phillip D, et al. Attenuation of spinal cord ischemia-reperfusion injury by specific alpha-2a receptor activation with dexmedetomidine[J]. J Vasc Surg, 2012, 56(5): 1398-1402.

6. Uysal Hale Yarkan, Cuzdan Suat Sedat, Kayiran Oguz, et al. Preventive effect of dexmedetomidine in ischemia-reperfusion injury[J]. J Craniofac Surg, 2012, 23(5): 1287-1291.

7. Kilic Kemal, Hanci Volkan, Selek Sahbettin, et al. The effects of dexmedetomidine on mesenteric arterial occlusion-associated gut ischemia and reperfusion-induced gut and kidney injury in rabbits[J]. J Surg Res, 2012, 178(1): 223-232.

8. 刘学升. 缺血性脑血管病的病理生理[M]//邢成名. 缺血性脑血管病.第一版. 北京: 人民卫生出版社，2003: 110-153.

9. 任长和, 欧册华. 右美托咪啶脑保护作用的研究进展[J]. 医学综述, 2012, 18(5): 721-723.

10. 张挺, 李丽琴. α2肾上腺素受体的结构及其生物学功能[J]. 生命的化学, 2006, 26(3): 266-269.

11. Cotecchia Susanna, Kobilka Brain K, Daniel Kiefer W, et al. Multiple second messenger pathways of α-adrenergic receptor subtypes expressed in eukaryotic cells[J]. J Biol Chem, 1990, 265(1): 63-69.

12. Hayashi Yukio, Rabin Bradford C, Guo Tianzhi, et al. Role of pertussis toxin-sensitive G-proteins in the analgesic and anesthetic actions of α2-adrenergic agonists in the rat[J]. Anesthesiology, 1995, 83(4): 816-822.

13. 郭荣, 程芮. 右美托咪定对脑缺血性损伤的保护作用[J]. 中国新药与临床杂志, 2012, 31(4): 197-201.

14. Ostopovici-Halip Liliana, Curpan Ramona, Mracec Maria, et al. Structural determinants of the alpha2 adrenoceptor subtype selectivity[J]. J Mol Graph Model, 2011, 29(8): 1030-1038.

15. Casanovas Anna, Olmos Gabriel, Ribera Joan, et al. Induction of reactive astrocytosis and prevention of motoneuron cell death by the I2-imidazoline receptor ligand LSL 60101[J]. Br J Pharmacol, 2000, 130(8): 1767-1776.

16. 苏瑞斌, 李锦. 咪唑啉I2受体研究进展[J]. 中国药理学与毒理学杂志, 2004, 18(1): 75-78.

17. Broughton Brad R, Reutens David C, Sobey Christopher G. Apoptotic mechanisms after cerebral ischemia[J]. Stroke, 2009, 40(5): e331-e339.

18. Scanziani Massimo, Gahwiler Beat H, Thompson Scott M. Presynaptic inhibition of excitatory synaptic transmission mediated by α adrenergic receptors in area CA3 of the rat hippocampus in vitro[J]. J Neurosci, 1993, 13(12): 5393-5401.

19. Boehm Stefan. Presynaptic α2-adrenoceptors control excitatory, but not inhibitory, transmission at rat hippocampal synapses[J]. J Physiol, 1999, 519(2): 439-449.

20. Berkman M Zafer, Zirh T Ali, Berkman Kemal, et al. Tizanidine is an effective agent in the prevention of focal cerebral ischemia in rats: an experimental study[J]. Surg Neurol, 1998, 50(3): 264-270.

21. Jellish W Scott, Murdoch John, Kindel Gisela, et al. The effect of clonidine on cell survival, glutamate, and aspartate release in normo- and hyperglycemic rats after near complete forebrain ischemia[J]. Exp Brain Res, 2005, 167(4): 526-534.

22. Chiu Kuanming, Lin Tzuyu, Lu Chengwei, et al. Inhibitory effect of glutamate release from rat cerebrocortical nerve terminals by alpha2 adrenoceptor agonist dexmedetomidine[J]. Eur J Pharmacol, 2011, 670(1): 137-147.

23. Huang Rong, Chen Ye, Yu A C, et al. Dexmedetomidine-induced stimulation of glutamine oxidation in astrocytes: a possible mechanism for its neuroprotective activity[J]. J Cereb Blood Flow Metab, 2000, 20(6): 895-898.

24. Engelhard Kristin, Werner Christian, Kaspar Susanne, et al. Effect of the alpha2-agonist dexmedetomidine on cerebral neurotransmitter concentrations during cerebral ischemia in rats[J]. Anesthesiology, 2002, 96(2): 450-457.

25. Simonson Steven G, Zhang Jing, Canada Andrew T Jr, et al. Hydrogen peroxide production by monoamine oxidase during ischemia-reperfusion in the rat brain[J]. J Cereb Blood Flow Metab, 1993, 13(1): 125-134.

26. Langer S Z. Presynaptic regulation of the release of catecholamines[J]. Pharmacol Rev, 1980, 32(4): 337-362.

27. Kuhmonen Johanna, Pokorny Jaroslav, Miettinen Riitta, et al. Neuroprotective effects of dexmedetomidine in the gerbil hippocampus after transient global ischemia[J]. Anesthesiology, 1997, 87(2): 371-377.

28. Nacif-Coelho Carla, Correa-Sales Christiane, Chang Louise Lenoir, et al. Perturbation of ion channel conductance alters the hypnotic response to the alpha 2-adrenergic agonist dexmedetomidine in the locus coeruleus of the rat[J]. Anesthesiology, 1994, 81(6): 1527-1534.

29. Gorini A, Villa Roberto Federico. Effect of in vivo treatment of clonidine on ATP-ase's enzyme systems of synaptic plasma membranes from rat cerebral cortex[J]. Neurochem Res, 2001, 26(7): 821-827.

30. Eser Olcay, Fidan Huseyin, Sahin Onder, et al. The influence of dexmedetomidine on ischemic rat hippocampus[J]. Brain Res, 2008, 1218: 250-256.

31. Engelhard Kristin, Werner Christian, Eberspacher Eva, et al. The effect of the alpha 2-agonist dexmedetomidine and the N-methyl-D-aspartate antagonist S(+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats[J]. Anesth Analg, 2003, 96(2): 524-531.

32. Sanders R D, Sun P, Patel S, et al. Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain[J]. Acta Anaesthesiol Scand, 2010, 54(6): 710-716.

33. Dahmani Souhayl, Rouelle Danielle, Gressens Pierre, et al. Effects of dexmedetomidine on hippocampal focal adhesion kinase tyrosine phosphorylation in physiologic and ischemic conditions[J]. Anesthesiology, 2005, 103(5): 969-977.

34. 吕佩源, 胡亚卓, 肖向建, 等. 血管性痴呆小鼠海马ERK2及p-ERK的表达特征[J]. 神经疾病与精神卫生, 2007, 7(4): 251-253.

35. Dahmani Souhayl, Paris Andrea, Jannier Virginie, et al. Dexmedetomidine increases hippocampal phosphorylated extracellular signal-regulated protein kinase 1 and 2 content by an α2-adrenoceptor-independent mechanism: evidence for the involvement of imidazoline I1 receptors[J]. Anesthesiology, 2008, 108(3): 457-466.

36. Schoeler Marc, Loetscher Philip D, Rossaint Rolf, et al. Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury[J]. BMC Neurol, 2012, 12(1): 20.

37. 韩新生, 吕建瑞, 张珍妮, 等. ERK抑制剂PD98059对SD大鼠全脑缺血再灌注后海马Caspase-3表达的影响[J]. 山西医科大学学报, 2012, 43(2): 81-84.

38. 路文婷, 陈朝旺, 高俊玲. 大鼠脑创伤后ERK信号转导通路对神经细胞凋亡的影响[J]. 中国医药导报, 2012, 9(18): 39-41.

39. 牛非, 胡金凤, 苑玉和, 等. 星形胶质细胞在脑缺血中的变化和作用[J]. 中国药理学通报, 2011, 27(10): 1342-1345.

40. Qu Yi, Duan Zhou-jin, Zhao Feng-yan, et al. Telomerase reverse transcriptase upregulation attenuates astrocyte proliferation and promotes neuronal survival in the hypoxic-ischemic rat brain[J]. Stroke, 2011, 42(12): 3542-3550.

41. 沙晶, 朱沂, 党辉, 等. 脑缺血/再灌注损伤对小鼠海马区胶质细胞的影响[J]. 新疆医科大学学报, 2012, 35(2): 158-162.

42. Zhao Z, Code W E, Hertz L. Dexmedetomidine, a potent and highly specific alpha 2 agonist, evokes cytosolic calcium surge in astrocytes but not in neurons[J]. Neuropharmacology, 1992, 31(10): 1077-1079.

43. Huang Rong, Hertz Leif. Clonidine enhances astrocytic glutamine uptake by authentic alpha 2-adrenoceptor stimulation[J]. Neuroreport, 1994, 5(5): 632-634.

44. Yan Min, Dai Hai-bin, Ding Ting-ting, et al. Effects of dexmedetomidine on the release of glial cell line-derived neurotrophic factor from rat astrocyte cells[J]. Neurochem Int, 2011, 58(5): 549-557.

45. Reis D J, Regunathan S, Golanov E V, et al. Protection of focal ischemic infarction by rilmenidine in the animal: evidence that interactions with central imidazoline receptors may be neuroprotective[J]. Am J Cardiol, 1994, 74(13): 25A-30A.

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