药学学报, 2017, 52(6): 928-935
引用本文:
刘冬梅, 张蔓, 江晓妹, 雷慧, 李江, 王晓良. 多奈哌齐和加兰他敏对氧糖剥夺/复氧导致的神经元损伤的保护作用及机制[J]. 药学学报, 2017, 52(6): 928-935.
LIU Dong-mei, ZHANG Man, JIANG Xiao-mei, LEI Hui, LI Jiang, WANG Xiao-liang. Protective effects and the mechanisms of donepezil and galantamine on neuronal injury induced by glucose deprivation/reoxygenation[J]. Acta Pharmaceutica Sinica, 2017, 52(6): 928-935.

多奈哌齐和加兰他敏对氧糖剥夺/复氧导致的神经元损伤的保护作用及机制
刘冬梅, 张蔓, 江晓妹, 雷慧, 李江, 王晓良
中国医学科学院, 北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
摘要:
已有研究表明乙酰胆碱酯酶抑制剂多奈哌齐和加兰他敏具有减轻氧糖剥夺导致的神经元损伤并减小脑缺血动物的脑梗死体积的作用,但它们的这种作用可能并不完全依赖于其胆碱酯酶抑制活性。为了进一步研究多奈哌齐和加兰他敏对脑缺血后神经元损伤的作用,本课题组成功建立了体外大鼠神经元-星形胶质细胞共培养模型,并在该共培养模型的基础上研究多奈哌齐和加兰他敏对氧糖剥夺/复氧(oxygen-glucose deprivation/reoxygenation,OGD/R)后神经元凋亡的作用及其可能的作用机制。结果表明,多奈哌齐和加兰他敏可以明显减轻OGD/R后共培养体系中的神经元凋亡,同时,促进共培养体系中星形胶质细胞合成和分泌BDNF和NGF,并激活星形胶质细胞内的PI3K/Akt通路和ERK通路,促进核转录因子CREB的磷酸化。以上结果说明多奈哌齐和加兰他敏对OGD/R导致的神经元损伤具有保护作用,其机制可能与激活星形胶质细胞内的PI3K/Akt通路和ERK通路,促进核转录因子CREB的磷酸化,进而促进星形胶质细胞合成和分泌BDNF和NGF有关。
关键词:    多奈哌齐      加兰他敏      神经元凋亡      星形胶质细胞      神经营养     
Protective effects and the mechanisms of donepezil and galantamine on neuronal injury induced by glucose deprivation/reoxygenation
LIU Dong-mei, ZHANG Man, JIANG Xiao-mei, LEI Hui, LI Jiang, WANG Xiao-liang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Studies have shown that acetylcholinesterase inhibitors donepezil and galantamine have effects of reducing neuronal damage caused by glucose deprivation and reducing the cerebral infarction volume of cerebral ischemic animals, but their effects may not be entirely dependent on its inhibition of cholinesterase activity. In order to study the effects of donepezil and galantamine on neuronal injury of cerebral ischemia, the rat neuron-astrocyte co-culture model was successfully established in this study. In this model, we studied the effects of donepezil and galantamine on neuron apoptosis induced by oxygen-glucose deprivation/reoxygenation (OGD/R) and investigated the mechanism. The results showed that donepezil and galantamine significantly reduced the neuron apoptosis, and promoted the synthesis and secretion of BDNF and NGF in astrocytes in the co-culture system. Donepezil and galantamine activated the PI3K/Akt pathway and ERK pathway, and promoted the phosphorylation of the nuclear transcription factor CREB. These results suggest that donepezil and galantamine exhibit protective effects on neuronal damage induced by OGD/R. The mechanism may be related to activation of PI3K/Akt pathway and ERK pathway in astrocytes and promote phosphorylation of CREB, which lead to the synthesis and secretion of BDNF and NGF from astrocytes.
Key words:    donepezil    galantamine    neuron apoptosis    astrocyte    neurotrophy   
收稿日期: 2017-05-15
DOI: 10.16438/j.0513-4870.2017-0485
基金项目: 国家自然科学基金资助项目(81573417)
通讯作者: 王晓良,Tel:86-10-63165183,E-mail:wangxl@imm.ac.cn
Email: wangxl@imm.ac.cn
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参考文献:
[1] Lorrio S, Sobrado M, Arias E, et al. Galantamine postischemia provides neuroprotection and memory recovery against tran­sient global cerebral ischemia in gerbils [J]. J Pharmacol Exp Ther, 2007, 322: 591-599.
[2] Zhou J, Fu Y, Tang XC. Nuperzine A and donepezil protect rat pheochromocytoma cells against oxygen-glucose depriva­tion [J]. Neurosci Lett, 2001, 306: 53-56.
[3] Akasofu S, Kosasa T, Kimura M. Protective effect of donepezil in a primary culture of rat cortical neurons exposed to oxygen-glucose deprivation [J]. Eur J Pharmacol, 2003, 472: 57-63.
[4] Jana M, Jana A, Pal U, et al. A simplified method for isolating highly purified neurons, oligodendrocytes, astrocytes, and microglia from the same human fetal brain tissue [J]. Neurochem Res, 2007, 32: 2015-2022.
[5] Kaech S, Banker G. Culturing hippocampal neurons [J]. Nat Protoc, 2006, 1: 2406-2415.
[6] Falcao AS, Silva RF, Vaz AR, et al. Cross-talk between neurons and astrocytes in response to bilirubin: adverse secondary impacts [J]. Neurochem Res, 2013, 38: 644-659.
[7] Madrigal JL, Leza JC, Polak P, et al. Astrocyte-derived MCO-1 mediates neuroprotective effects of noradrenaline [J]. J Neurosci, 2009, 29: 263-267.
[8] Tonchev AB. Brain ischemia, neurogenesis, and neurotrophic receptor expression in primates [J]. Arch Ital Biol, 2011, 149: 225-231.
[9] Yamaguchi H, Wang HG. The protein kinase PKB/Akt regu­lates cell survival and apoptosis by inhibiting Bax conforma­tional change [J]. Oncogene, 2001, 20: 7779-7786.
[10] Nair A, Vadodaria KC, Banerjee SB, et al. Stressor-specific regulation of distinct brain-derived neurotrophic factor tran­scripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus [J]. Nuropsychopharmacology, 2007, 32: 1504-1519.
[11] Numakawa T, Suzuki S, Kumamaru E, et al. BDNF function and intracellular signaling in neurons [J]. Histol Histopathol, 2010, 25: 237-258.
[12] Garat CV, Crossno JT Jr, Sullivan TM, et al. Inhibition of phosphatidylinositol 3-kinase/Akt signaling attenuates hypoxia-induced pulmonary artery remodeling and suppresses CREB depletion in arterial smooth muscle cells [J]. J Cardiovasc Pharmacol, 2013, 62: 539-548.
[13] Yuan H, Wang WP, Feng N, et al. Donepezil attenuated oxygen-glucose deprivation insulty by blocking Kv2.1 potas­sium channels [J]. Eur J Pharmacol, 2011, 657: 76-83.
[14] Pan Y, Xu X, Wang X. Rivastigmine blocks voltage-activated K+ currents in dissociated rat hippocampal neurons [J]. Br J Pharmacol, 2003, 140: 907-912.
[15] Solntseva EI, Bukanova JV, Skrebitsky VG. Donepezil in low micromolar concentrations modulates voltage-gated potas­sium currents in pyramidal neurons of rat hippocampus [J]. Biochem Biophys Res Commun, 2013, 430: 1066-1071.
[16] Yu B, Hu GY. Donepezil blocks voltage-gated ion channels in rat dissociated hippocampal neurons [J]. Eur J Pharmacol, 2005, 508: 15-21.
[17] Zhang HX, Zhang W, Jin HW, et al. Galantamine blocks cloned Kv2.1, but not Kv1.5 potassium channels [J]. Brain Res Mol Brain Res, 2004, 131: 136-140.
[18] Pan YP, Xu XH, Wang XL. Galantamine blocks delayed rectifier, but not transient outward potassium current in rat dissociated hippocampal pyramidal neurons [J]. Neurosci Lett, 2003, 336: 37-40.
[19] Kraliz D, Singh S. Selective blockade of the delayed rectifier potassium current by tacrine in Drosophila [J]. J Neurobiol, 1997, 32: 1-10.