生长激素促泌素与帕金森病关系的研究进展
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摘要
帕金森病(PD)是一种常见于中老年的神经系统变性疾病,黑质多巴胺神经元变性坏死、多巴胺递质的失衡为主要病理改变。生长激素促泌素是一种生长激素释放肽,是目前发现的生长激素促泌素受体(GHSR)的唯一内源性配体,其与GHSR结合后会产生生物学作用,例如促进生长激素的释放,促进摄食,调节能量代谢以及保护心血管系统等。大量的实验还发现在PD中,生长激素促泌素对黑质多巴胺神经元具有保护作用、促进多巴胺释放、对多巴胺神经元具有兴奋作用,并能缓解PD患者的临床症状,本综述将总体介绍PD与生长激素促泌素的研究进展,并为相关的科学研究提供基础资料。
Parkinson's disease(PD) is a common neurodegenerative disease in the elderly,the main pathological changes being dopaminergic neurons degeneration and necrosis and imbalance of dopamine.Growth hormone secretagogue(ghrelin) is a growth hormone releasing peptide,which is currently only one endogenous ligand receptor of ghrelin found now,can produce biological effects by binding the receptor,such as promoting the release of growth hormone,promoting food intake,regulating metabolism and protecting the cardiovascular system.Recently a large number of experiments in PD found that the hormone has a protective effect,promoting dopamine release,exciting dopaminergic neurons and relieving the clinical symptoms of PD patients.The overall research progress of PD and ghrelin were reviewed and the basic research related data was provided.
Parkinson's disease(PD) is a common neurodegenerative disease in the elderly,the main pathological changes being dopaminergic neurons degeneration and necrosis and imbalance of dopamine.Growth hormone secretagogue(ghrelin) is a growth hormone releasing peptide,which is currently only one endogenous ligand receptor of ghrelin found now,can produce biological effects by binding the receptor,such as promoting the release of growth hormone,promoting food intake,regulating metabolism and protecting the cardiovascular system.Recently a large number of experiments in PD found that the hormone has a protective effect,promoting dopamine release,exciting dopaminergic neurons and relieving the clinical symptoms of PD patients.The overall research progress of PD and ghrelin were reviewed and the basic research related data was provided.
引文
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[28]Bayliss JA,Lemus MB,Stark R,et al.Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease[J].JNeurosci,2016,36:3049-3063
[29]Jiang H,Li LJ,Wang J,et al.Ghrelin antagonizes MPTP-induced neurotoxicity to the dopaminergic neurons in mouse substantia nigra[J].Exp Neurol,2008,212:532-537
[30]Dong J,Song N,Xie J,et al.Ghrelin antagonized l-methyl-4-phenylpyridinium(MPP(+))-induced apoptosis in MES23.5 cells[J].J Mol Neurosci,2009,37:182-189
[31]Liu L,Xu H,Jiang H,et al.Ghrelin prevents l-methyl-4-phenylpyridinium ion-induced cytotoxicity through antioxidation and NF-kB modulation in MES23.5 cells[J].Exp Neurol,2010,222:25-29
[32]董娟娟.Ghrelin对MPP+诱导的MES23.5细胞凋亡的保护作用及可能机制的探讨[D].青岛大学,2009.
[33]Fujitsuka N,Asakawa A,Morinaga A,et al.Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuinl[J].Mol Psychiatry,2016,21:1613-1623
[34]Yu J,Xu H,Shen X,et al.Ghrelin protects MES23.5 cells against rotenone via inhibiting mitochondrial dysfunction and apoptosis[J].Neuropeptides,2016,56:69-74
[35]McCarty MF.Potential ghrelin-mediated benefits and risks of hydrogen water[J].Med Hypotheses,2015,84:350-355
[36]Moon M,Kim HG,Hwang L,et al.Neuroprotective effect of ghrelin in the l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine mouse model of Parkinson's disease by blocking microglial activation[J].Neurotox Res,2009,15:332-347
[37]Isgaard J.Ghrelin and the cardiovascular system[J].Endocrine Development,2013,25:83-90
[38]Andrews ZB,Erion D,Beiler R,et al.Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism[J].J Neurosci,2009,29:14057-14065
[39]Dezaki K,Sone H,Koizumi M,et al.Blockade of pancreatic isletderived ghrelin enhances insulin secretion to prevent high-fat dietinduced glucose intolerance[J].Diabetes,2006,55:3486-3493
[40]Wellman PJ,Davis KW,Nation JR.Augmentation of cocaine hyperactivity in rats by systemic ghrelin[J].Regul Pept,2005,125:15115-15124
[41]Osterstock G,Escobar P,Mitutsova V,et al.Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus[J].PLoS One,2010,5:e9l59
[42]Han XF,Zhu YL,Hernandez M,et al.Ghrelin reduces voltagegated potassium currents in GH3 cells via cyclic GMP pathways[J].Endocrine,2005,28:217-224
[43]Quarta D,Di Francesco C,Melotto S,et al.Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens[J].Neurochem Int,2009,54:89-94
[44]石丽敏.GHRELIN对黑质多巴胺能神经元的调制作用及其生物学意义探讨[D].青岛大学,2011.
[45]Weikel JC,Wichniak A,Ising M,et al.Ghrelin promotes slowwave sleep in humans[J].Am J Physiol Endocrinol Metab,2003,284:E407-E415
[46]Bodosi B,Gardi J,Hajdu I,et al.Rhythms of ghrelin,leptin,and sleep in rats:effects of the normal diurnal cycle,restricted feeding,and sleep deprivation[J].Am J Physiol Regul lntegr Comp Physiol,2004,287:R1071-1079
[47]Harsch IA,Konturek PC,Koebnick C,et al.Leptin and ghrelin levels in patients with obstructive sleep apnoea:effect of CPAP treatment[J].Eur Respir J,2003,22:251-257
[48]Gaston MS,Cid MP,Salvatierra NA.Bicuculline,a GABAA-receptor antagonist,blocked HPA axis activation induced by ghrelin under an acute stress[J].Behav Brain Res,2016,pii:S0166-4328
[2]Molloy S,McKeith 1G,O'Brien JT,et al.The role of levodopa in the management of dementia with Lewy bodies[J].J Neurol Neurosurg Psychiatry,2005,76:1200-1203
[3]Jankovic J.Parkinson's disease:clinical features and diagnosis[J].J Neurol Neurosurg Psychiatry,2008,79:368-376
[4]Verschuur CV,Suwijn SR,Post B,et al.Protocol of a randomised delayed-start double-blind placebo-controlled multi-centre trial for Levodopa in EArly Parkinson's disease:the LEAP-study[J].BMC Neurol,2015,15:236
[5]Wellman M,Abizaid A.Growth Hormone Secretagogue Receptor Dimers:A New Pharmacological Target(l,2,3)[J].eNeuro,2015,2(2).
[6]Merajoth AL,Pillai PS,lype T.Clinical Response of Levodopa Carbidopa Combination in Patients with Idiopathic Parkinsonism[J].J Clin Diagn Res,2016,10:FC07-10
[7]Pezzoli G,Zini M.Levodopa in Parkinson's disease:from the past to the future[J].Expert Opin Pharmacother,2010,l 1:627-635
[8]Jankovic J,Aguilar LG.Current approaches to the treatment of Parkinson's disease[J].Neuropsychiatr Dis Treat,2008,4:743-757
[9]Bowers CY,Momany F,Reynolds GA,et al.Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro[J].Endocrinology,1980,106:663-667
[10]Park JH,Kim JW,Park JK,et al.[Current Status of Translational Research on Functional Dyspepsia][J].Korean J Gastroenterol,2016,68:132-137
[11]Bayliss JA,Lemus M,Santos VV,et al.Acylated but not des-acyl ghrelin is neuroprotective in an MPTP mouse model of Parkinson's disease[J].J Neurochem,2016,137:460-471
[12]Tschop M,Wawarta R,Riepl RL,et al.Post-prandial decrease of circulating human ghrelin levels[J].J Endocrinol Invest,2001,24:RC19-21
[13]Sato T,Fukue Y,Teranishi H,et al.Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-d-glucose administration[J].Endocrinology,2005,146:2510-2516
[14]Kanamoto N,Akamizu T,Hosoda H,et al.Substantial production of ghrelin by a human medullary thyroid carcinoma cell line[J].J Clin Endocrinol Metab,2001,86:4984-4990
[15]Kishimoto M,Okimura Y,Nakata H,et al.Cloning and characterization of the 5(')-flanking region of the human ghrelin gene[J].Biochem Biophys Res Commun,2003,305:186-192
[16]Gálfi M,Radacs M,Molnar Z,et al.Ghrelin-lnduced Enhancement of Vasopressin and Oxytocin Secretion in Rat Neurohypophyseal Cell Cultures[J].J Mol Neurosci,2016,60:525-530
[17]管洪在.迷走复合体注射GHRELIN激活弓状核NPY,AGRP神经元而诱发多食[D].青岛大学,2011.
[18]Shi L,Du X,Jiang H,et al.Ghrelin and Neurodegenerative Disorders-a Review[J].Mol Neurobiol,2016:1-12
[19]Lufrano D,Trejo SA,Llovera RE,et al.Ghrelin binding to serum albumin and its biological impact[J].Mol Cell Endocrinol,2016,436:130-140
[20]Tokudome T,Kishimoto I,Miyazato M,et al."Ghrelin and the cardiovascular system,"Cardiovascular Issues in Endocrinology[M].Karger Publishers,2014,43:125-133
[21]Barboza JL,Okun MS,Moshiree B.The treatment of gastroparesis,constipation and small intestinal bacterial overgrowth syndrome in patients with Parkinson's disease[J].Expert Opin Pharmacother,2015,16:2449-2464
[22]Baldanzi G,Filigheddu N,Cutrupi S,et al.Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT[J].J Cell Biol,2002,159:1029-1037
[23]Diano S,Farr SA,Benoit SC,et al.Ghrelin controls hippocampal spine synapse density and memory performance[J].Nat Neurosci,2006,9:381-388
[24]Schtissler P,Uhr M,Ising M,et al.Nocturnal ghrelin,ACTH,GH and Cortisol secretion after sleep deprivation in humans[J].Psychoneuroen docrinology,2006,31:915-923
[25]Lutter M,Sakata I,Osborne-Lawrence S,et al.The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress[J].Nat Neurosci.2008,11:752-753
[26]Liu Y,Chen L,Xu X,et al.Both ischemic preconditioning and ghrelin administration protect hippocampus from ischemia/reperfusion and upregulate uncoupling protein-2[J].BMC physiol,2009,9:17
[27]Shi L,Du X,Jiang H,et al.Ghrelin and Neurodegenerative Disorders-a Review[J].Mol Neurobiol,2016:l-12
[28]Bayliss JA,Lemus MB,Stark R,et al.Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease[J].JNeurosci,2016,36:3049-3063
[29]Jiang H,Li LJ,Wang J,et al.Ghrelin antagonizes MPTP-induced neurotoxicity to the dopaminergic neurons in mouse substantia nigra[J].Exp Neurol,2008,212:532-537
[30]Dong J,Song N,Xie J,et al.Ghrelin antagonized l-methyl-4-phenylpyridinium(MPP(+))-induced apoptosis in MES23.5 cells[J].J Mol Neurosci,2009,37:182-189
[31]Liu L,Xu H,Jiang H,et al.Ghrelin prevents l-methyl-4-phenylpyridinium ion-induced cytotoxicity through antioxidation and NF-kB modulation in MES23.5 cells[J].Exp Neurol,2010,222:25-29
[32]董娟娟.Ghrelin对MPP+诱导的MES23.5细胞凋亡的保护作用及可能机制的探讨[D].青岛大学,2009.
[33]Fujitsuka N,Asakawa A,Morinaga A,et al.Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuinl[J].Mol Psychiatry,2016,21:1613-1623
[34]Yu J,Xu H,Shen X,et al.Ghrelin protects MES23.5 cells against rotenone via inhibiting mitochondrial dysfunction and apoptosis[J].Neuropeptides,2016,56:69-74
[35]McCarty MF.Potential ghrelin-mediated benefits and risks of hydrogen water[J].Med Hypotheses,2015,84:350-355
[36]Moon M,Kim HG,Hwang L,et al.Neuroprotective effect of ghrelin in the l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine mouse model of Parkinson's disease by blocking microglial activation[J].Neurotox Res,2009,15:332-347
[37]Isgaard J.Ghrelin and the cardiovascular system[J].Endocrine Development,2013,25:83-90
[38]Andrews ZB,Erion D,Beiler R,et al.Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism[J].J Neurosci,2009,29:14057-14065
[39]Dezaki K,Sone H,Koizumi M,et al.Blockade of pancreatic isletderived ghrelin enhances insulin secretion to prevent high-fat dietinduced glucose intolerance[J].Diabetes,2006,55:3486-3493
[40]Wellman PJ,Davis KW,Nation JR.Augmentation of cocaine hyperactivity in rats by systemic ghrelin[J].Regul Pept,2005,125:15115-15124
[41]Osterstock G,Escobar P,Mitutsova V,et al.Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus[J].PLoS One,2010,5:e9l59
[42]Han XF,Zhu YL,Hernandez M,et al.Ghrelin reduces voltagegated potassium currents in GH3 cells via cyclic GMP pathways[J].Endocrine,2005,28:217-224
[43]Quarta D,Di Francesco C,Melotto S,et al.Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens[J].Neurochem Int,2009,54:89-94
[44]石丽敏.GHRELIN对黑质多巴胺能神经元的调制作用及其生物学意义探讨[D].青岛大学,2011.
[45]Weikel JC,Wichniak A,Ising M,et al.Ghrelin promotes slowwave sleep in humans[J].Am J Physiol Endocrinol Metab,2003,284:E407-E415
[46]Bodosi B,Gardi J,Hajdu I,et al.Rhythms of ghrelin,leptin,and sleep in rats:effects of the normal diurnal cycle,restricted feeding,and sleep deprivation[J].Am J Physiol Regul lntegr Comp Physiol,2004,287:R1071-1079
[47]Harsch IA,Konturek PC,Koebnick C,et al.Leptin and ghrelin levels in patients with obstructive sleep apnoea:effect of CPAP treatment[J].Eur Respir J,2003,22:251-257
[48]Gaston MS,Cid MP,Salvatierra NA.Bicuculline,a GABAA-receptor antagonist,blocked HPA axis activation induced by ghrelin under an acute stress[J].Behav Brain Res,2016,pii:S0166-4328