AMPK在缺血性脑卒中中的研究进展

doi:10.3969/j.issn.1006-9771.2020.12.008

摘要/Abstract

摘要：

AMP激活的蛋白激酶(AMPK)是一种进化保守的丝氨酸/苏氨酸激酶,在调节全身细胞能量代谢的稳态中起着至关重要的作用。在正常生理情况下,AMPK能够促进大脑发育和调节神经元极化。在缺血性脑卒中中,AMPK的上调可以减弱氧化应激,抑制神经炎症,调节神经元自噬和凋亡,改善线粒体功能,抑制谷氨酸兴奋性毒性和促进新生血管形成等。AMPK在缺血性脑卒中的治疗中具有促进功能恢复的作用,主要形式包括药物治疗、物理疗法和受体靶向治疗。但靶向AMPK的应用在临床中的证据和机制依然不是很充足,有待进一步研究。

关键词: 缺血性脑卒中, AMP激活的蛋白激酶, 能量传感器, 靶点, 综述

Abstract:

AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that plays a vital role in regulating the homeostasis of cellular energy metabolism. Under normal physiological conditions, AMPK can promote brain development and regulate neuronal polarization. In ischemic stroke, the upregulation of AMPK can reduce oxidative stress, inhibit neuroinflammation, regulate neuronal autophagy and apoptosis, improve mitochondrial function, inhibit glutamate excitotoxicity and promote neovascularization. AMPK can promote functional recovery in the treatment of ischemic stroke. The current treatment methods based on AMPK mainly include drug therapy, physical therapy and receptor targeted therapy. However, the evidence and mechanism of the application of targeting AMPK in the clinic are still not sufficient, and need further research.

Key words: ischemic stroke, AMP-activated protein kinase, energy sensor, target, review

中图分类号:

R743.3

刘伟,唐蓉,张晶玉,王迎斌. AMPK在缺血性脑卒中中的研究进展[J]. 《中国康复理论与实践》, 2020, 26(12): 1422-1426.

LIU Wei,TANG Rong,ZHANG Jing-yu,WANG Ying-bin. Advance of AMPK in Ischemic Stroke (review)[J]. 《Chinese Journal of Rehabilitation Theory and Practice》, 2020, 26(12): 1422-1426.

参考文献 44

[1]	罗媛媛, 安丙辰, 郑洁皎. 八段锦在脑卒中康复中的应用进展[J]. 中国康复理论与实践, 2019, 25(9):1057-1059.
	Luo Y Y, An B C, Zheng J J. Advance in Baduanjin for rehabilitation of stroke (review)[J]. Chin J Rehabil Theory Pract, 2019, 25(9):1057-1059.
[2]	Chehaibi K, Trabelsi I, Mahdouani K, et al. Correlation of oxidative stress parameters and inflammatory markers in ischemic stroke patients[J]. J Stroke Cerebrovasc Dis, 2016, 25(11):2585-2593. doi: 10.1016/j.jstrokecerebrovasdis.2016.06.042
[3]	Gu C, Li T, Jiang S, et al. AMP-activated protein kinase sparks the fire of cardioprotection against myocardial ischemia and cardiac ageing[J]. Ageing Res Rev, 2018, 47:168-175. doi: 10.1016/j.arr.2018.08.002
[4]	Hardie D G, Schaffer B E, Brunet A. AMPK: an energy-sensing pathway with multiple inputs and outputs[J]. Trends Cell Biol, 2016, 26(3):190-201. doi: 10.1016/j.tcb.2015.10.013
[5]	Moreira D, Silvestre R, Cordeiro-Da-Silva A, et al. AMP-activated protein kinase as a target for pathogens: friends or foes?[J]. Curr Drug Targets, 2016, 17(8):942-953. pmid: 25882224
[6]	Salt I P, Hardie D G. AMP-activated protein kinase: an ubiquitous signaling pathway with key roles in the cardiovascular system[J]. Circ Res, 2017, 120(11):1825-1841. doi: 10.1161/CIRCRESAHA.117.309633 pmid: 28546359
[7]	Jiang S, Li T, Yang Z, et al. AMPK orchestrates an elaborate cascade protecting tissue from fibrosis and aging[J]. Ageing Res Rev, 2017, 38:18-27. doi: 10.1016/j.arr.2017.07.001
[8]	Marinangeli C, Didier S, Vingtdeux V. AMPK in neurodegenerative diseases: implications and therapeutic perspectives[J]. Curr Drug Targets, 2016, 17(8):890-907. pmid: 26073858
[9]	Gao G, Widmer J, Stapleton D, et al. Catalytic subunits of the porcine and rat 5'-AMP-activated protein kinase are members of the snf1 protein kinase family[J]. Biochim Biophys Acta, 1995, 1266(1):73-82. pmid: 7718624
[10]	Xue B, Kahn B B. AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues[J]. J Physiol, 2006, 574(Pt 1):73-83. doi: 10.1113/jphysiol.2006.113217
[11]	Dasgupta B, Milbrandt J. AMP-activated protein kinase phosphorylates retinoblastoma protein to control mammalian brain development[J]. Dev Cell, 2009, 16(2):256-270. doi: 10.1016/j.devcel.2009.01.005 pmid: 19217427
[12]	Arimura N, Kaibuchi K. Neuronal polarity: from extracellular signals to intracellular mechanisms[J]. Nat Rev Neurosci, 2007, 8(3):194-205. pmid: 17311006
[13]	Amato S, Liu X, Zheng B, et al. AMP-activated protein kinase regulates neuronal polarization by interfering with pi 3-kinase localization[J]. Science, 2011, 332(6026):247-251. doi: 10.1126/science.1201678
[14]	吴启超, 张妍, 张雯秀, 等. 利鲁唑治疗脊髓损伤的研究进展[J]. 中国康复理论与实践, 2018, 24(6):650-653.
	Wu Q C, Zhang Y, Zhang W X, et al. Advance in Riluzole for Spinal Cord Injury (review)[J]. Chin J Rehabil Theory Pract, 2018, 24(6):650-653.
[15]	Choi I Y, Ju C, Anthony Jalin A M, et al. Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury[J]. Am J Pathol, 2013, 182(3):928-939. doi: 10.1016/j.ajpath.2012.11.024
[16]	Blázquez C, Woods A, De Ceballos M L, et al. The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes[J]. J Neurochem, 1999, 73(4):1674-1682. pmid: 10501215
[17]	Xiong X Y, Liu L, Yang Q W. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke[J]. Prog Neurobiol, 2016, 142:23-44. doi: 10.1016/j.pneurobio.2016.05.001
[18]	Qiu J, Wang M, Zhang J, et al. The neuroprotection of sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling[J]. Int Immunopharmacol, 2016, 40:492-500. doi: 10.1016/j.intimp.2016.09.024
[19]	Liu Y, Tang G, Li Y, et al. Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion[J]. J Neuroinflammation, 2014, 11:177. doi: 10.1186/s12974-014-0177-4
[20]	Auriel E, Bornstein N M. Neuroprotection in acute ischemic stroke: current status[J]. J Cell Mol Med, 2010, 14(9):2200-2202. doi: 10.1111/j.1582-4934.2010.01135.x pmid: 20716132
[21]	鲁银山. 缺血性脑卒中后自噬活性变化的相关研究进展[J]. 中华物理医学与康复杂志, 2019, 41(9):703-707.
	Lu Y S. Chin J Phys Med Rehabil, 2019, 41(9):703-707.
[22]	Manwani B, Mccullough L D. Function of the master energy regulator adenosine monophosphate-activated protein kinase in stroke[J]. J Neurosci Res, 2013, 91(8):1018-1029. doi: 10.1002/jnr.23207 pmid: 23463465
[23]	Jiang T, Yu J T, Zhu X C, et al. Ischemic preconditioning provides neuroprotection by induction of AMP-activated protein kinase-dependent autophagy in a rat model of ischemic stroke[J]. Mol Neurobiol, 2015, 51(1):220-229. doi: 10.1007/s12035-014-8725-6 pmid: 24809692
[24]	Yang Y, Zhang X J, Li L T, et al. Apelin-13 protects against apoptosis by activating AMP-activated protein kinase pathway in ischemia stroke[J]. Peptides, 2016, 75:96-100. doi: 10.1016/j.peptides.2015.11.002 pmid: 26631263
[25]	Guo J M, Shu H, Wang L, et al. Sirt1-dependent AMPK pathway in the protection of estrogen against ischemic brain injury[J]. CNS Neurosci Ther, 2017, 23(4):360-369. doi: 10.1111/cns.2017.23.issue-4
[26]	Debalsi K L, Hoff K E, Copeland W C. Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases[J]. Ageing Res Rev, 2017, 33:89-104. doi: 10.1016/j.arr.2016.04.006
[27]	Toyama E Q, Herzig S, Courchet J, et al. Metabolism AMP-activated protein kinase mediates mitochondrial fission in response to energy stress[J]. Science, 2016, 351(6270):275-281. doi: 10.1126/science.aab4138
[28]	Ashabi G, Khodagholi F, Khalaj L, et al. Activation of AMP-activated protein kinase by metformin protects against global cerebral ischemia in male rats: interference of AMPK/PGC-1alpha pathway[J]. Metab Brain Dis, 2014, 29(1):47-58. doi: 10.1007/s11011-013-9475-2
[29]	Li Y, Li J, Li S, et al. Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK[J]. Toxicol Appl Pharmacol, 2015, 286(1):53-63. doi: 10.1016/j.taap.2015.03.010
[30]	Kuramoto N, Wilkins M E, Fairfax B P, et al. Phospho-dependent functional modulation of GABA(b) receptors by the metabolic sensor AMP-dependent protein kinase[J]. Neuron, 2007, 53(2):233-247. doi: 10.1016/j.neuron.2006.12.015
[31]	Hatakeyama M, Ninomiya I, Kanazawa M. Angiogenesis and neuronal remodeling after ischemic stroke[J]. Neural Regen Res, 2020, 15(1):16-19. doi: 10.4103/1673-5374.264442 pmid: 31535636
[32]	Jin Q, Cheng J, Liu Y, et al. Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke[J]. Brain Behav Immun, 2014, 40:131-142. doi: 10.1016/j.bbi.2014.03.003
[33]	Venna V R, Li J, Hammond M D, et al. Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke[J]. Eur J Neurosci, 2014, 39(12):2129-2138. doi: 10.1111/ejn.2014.39.issue-12
[34]	Wang L M, Wang Y J, Cui M, et al. A dietary polyphenol resveratrol acts to provide neuroprotection in recurrent stroke models by regulating AMPK and Sirt1 signaling, thereby reducing energy requirements during ischemia[J]. Eur J Neurosci, 2013, 37(10):1669-1681. doi: 10.1111/ejn.2013.37.issue-10
[35]	Tang H, Pan C S, Mao X W, et al. Role of NADPH oxidase in total salvianolic acid injection attenuating ischemia-reperfusion impaired cerebral microcirculation and neurons: implication of AMPK/AKT/PKC[J]. Microcirculation, 2014, 21(7):615-627. doi: 10.1111/micc.12140 pmid: 24702968
[36]	Chaturvedi S, Zivin J, Breazna A, et al. Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack[J]. Neurology, 2009, 72(8):688-694. doi: 10.1212/01.wnl.0000327339.55844.1a pmid: 18768917
[37]	Yu J, Wang W N, Matei N, et al. Ezetimibe attenuates oxidative stress and neuroinflammation via the AMPK/NRF2/TXNIP pathway after MCAO in rats[J]. Oxid Med Cell Longev, 2020, 2020:4717258.
[38]	宁文华, 李礼, 郭扬, 等. 电针预处理脑保护作用机制研究进展[J]. 中国康复理论与实践, 2019, 25(11):1315-1319.
	Ning W H, Li L, Guo Y, et al. Advance in brain protective mechanism of electroacupuncture preconditioning (review)[J]. Chin J Rehabil Theory Pract, 2019, 25(11):1315-1319.
[39]	李华南, 张海明, 顾兵, 等. 针刺促进脊髓损伤后神经功能恢复的机制及相关信号通路的作用[J]. 中国康复理论与实践, 2017, 23(6):641-644.
	Li H N, Zhang H M, Gu B, et al. Mechanism of acupuncture for recovery of neurological function after spinal cord injury and role of related signal pathway (review)[J]. Chin J Rehabil Theory Pract, 2017, 23(6):641-644.
[40]	Ran Q Q, Chen H L, Liu Y L, et al. Electroacupuncture preconditioning attenuates ischemic brain injury by activation of the adenosine monophosphate-activated protein kinase signaling pathway[J]. Neural Regen Res, 2015, 10(7):1069-1075. doi: 10.4103/1673-5374.160095
[41]	刘四维, 关敏, 高强. 任务导向性训练在脑卒中后偏瘫康复中的应用进展[J]. 中国康复医学杂志, 2020, 35(3):374-378.
	Liu S W, Guan M, Gao Q. Chin J Rehabil Med, 2020, 35(3):374-378.
[42]	龚文辉, 张素梅, 储珏. 有氧运动对饮食诱导的肥胖鼠下丘脑和褐色脂肪BMP7表达的影响[J]. 中国康复, 2016, 31(2):114-117.
	Gong W H, Zhang S M, Chu J. Effects of aerobic exercise on BMP7 protein expression in hypothalamus and brown adipose tissue in diet-induced obese rats[J]. Chin J Rehabil, 2016, 31(2):114-117.
[43]	Dornbos D 3rd., Zwagerman N, Guo M, et al. Preischemic exercise reduces brain damage by ameliorating metabolic disorder in ischemia/reperfusion injury[J]. J Neurosci Res, 2013, 91(6):818-827. doi: 10.1002/jnr.23203 pmid: 23553672
[44]	Li M, Zhao J, Hu Y, et al. Oxygen free radicals regulate energy metabolism via AMPK pathway following cerebral ischemia[J]. Neurol Res, 2010, 32(7):779-784. doi: 10.1179/174313209X459174