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http://dx.doi.org/10.4040/jkan.2019.49.3.317

Effect of Ghrelin on Memory Impairment in a Rat Model of Vascular Dementia  

Park, Jong-Min (College of Nursing Science, Kyung Hee University)
Kim, Youn-Jung (College of Nursing Science, Kyung Hee University)
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Journal of Korean Academy of Nursing / v.49, no.3, 2019 , pp. 317-328 More about this Journal
Abstract
Purpose: The purpose of this study was to identify the effect of ghrelin on memory impairment in a rat model of vascular dementia induced by chronic cerebral hypoperfusion. Methods: Randomized controlled groups and the posttest design were used. We established the representative animal model of vascular dementia caused by bilateral common carotid artery occlusion and administered $80{\mu}g/kg$ ghrelin intraperitoneally for 4 weeks. First, behavioral studies were performed to evaluate spatial memory. Second, we used molecular biology techniques to determine whether ghrelin ameliorates the damage to the structure and function of the white matter and hippocampus, which are crucial to learning and memory. Results: Ghrelin improved the spatial memory impairment in the Y-maze and Morris water maze test. In the white matter, demyelination and atrophy of the corpus callosum were significantly decreased in the ghrelin-treated group. In the hippocampus, ghrelin increased the length of hippocampal microvessels and reduced the microvessels pathology. Further, we confirmed angiogenesis enhancement through the fact that ghrelin treatment increased vascular endothelial growth factor (VEGF)-related protein levels, which are the most powerful mediators of angiogenesis in the hippocampus. Conclusion: We found that ghrelin affected the damaged myelin sheaths and microvessels by increasing angiogenesis, which then led to neuroprotection and improved memory function. We suggest that further studies continue to accumulate evidence of the effect of ghrelin. Further, we believe that the development of therapeutic interventions that increase ghrelin may contribute to memory improvement in patients with vascular dementia.
Keywords
Ghrelin; Dementia; Memory Disorders;
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1 Wang P, Xie ZH, Guo YJ, Zhao CP, Jiang H, Song Y, et al. VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer's disease. Biochemical and Biophysical Research Communications. 2011;411(3):620-626. https://doi.org/10.1016/j.bbrc.2011.07.003   DOI
2 Lopez NE, Krzyzaniak MJ, Blow C, Putnam J, Ortiz-Pomales Y, Hageny AM, et al. Ghrelin prevents disruption of the blood-brain barrier after traumatic brain injury. Journal of Neurotrauma. 2012;29(2):385-393. https://doi.org/10.1089/neu.2011.2053   DOI
3 Mead R. The design of experiments: Statistical principles for practical applications. Cambridge: Cambridge University Press; 1990. p. 7-8.
4 Spence KW, Lippitt R. An experimental test of the sign-gestalt theory of trial and error learning. Journal of Experimental Psychology. 1946;36(6):491-502. https://doi.org/10.1037/h0062419   DOI
5 Morris RGM, Garrud P, Rawlins JNP, O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature. 1982;297(5868):681-683. https://doi.org/10.1038/297681a0   DOI
6 Venkat P, Chopp M, Chen J. Models and mechanisms of vascular dementia. Experimental Neurology. 2015;272:97-108. https://doi.org/10.1016/j.expneurol.2015.05.006   DOI
7 Kim Y, Kim S, Kim C, Sato T, Kojima M, Park S. Ghrelin is required for dietary restriction-induced enhancement of hippocampal neurogenesis: Lessons from ghrelin knockout mice. Endocrine Journal. 2015;62(3):269-275. https://doi.org/10.1507/endocrj.EJ14-0436   DOI
8 Hansen TK, Dall R, Hosoda H, Kojima M, Kangawa K, Christiansen JS, et al. Weight loss increases circulating levels of ghrelin in human obesity. Clinical Endocrinology. 2002;56(2):203-206. https://doi.org/10.1046/j.0300-0664.2001.01456.x   DOI
9 Harvey J. Leptin regulation of neuronal morphology and hippocampal synaptic function. Frontiers in Synaptic Neuroscience. 2013;5:3. https://doi.org/10.3389/fnsyn.2013.00003   DOI
10 Irving AJ, Harvey J. Leptin regulation of hippocampal synaptic function in health and disease. Philosophical Transactions of the Royal Society B: Biological Sciences. 2014;369(1633):20130155. https://doi.org/10.1098/rstb.2013.0155   DOI
11 Li E, Kim Y, Kim S, Park S. Ghrelin-induced hippocampal neurogenesis and enhancement of cognitive function are mediated independently of GH/IGF-1 axis: Lessons from the spontaneous dwarf rats. Endocrine Journal. 2013;60(9):1065-1075. https://doi.org/10.1507/endocrj.ej13-0045   DOI
12 Chen L, Xing T, Wang M, Miao Y, Tang M, Chen J, et al. Local infusion of ghrelin enhanced hippocampal synaptic plasticity and spatial memory through activation of phosphoinositide 3‐kinase in the dentate gyrus of adult rats. European Journal of Neuroscience. 2011;33(2):266-275. https://doi.org/10.1111/j.1460-9568.2010.07491.x   DOI
13 Innocenti GM. General organization of callosal connections in the cerebral cortex. In: Jones EG, Peters A, editors. Sensory-Motor Areas and Aspects of Cortical Connectivity. Boston (MA): Springer US; 1986. p. 291-353.
14 Wu XP, Gao YJ, Yang JL, Xu M, Sun DH. Quantitative measurement to evaluate morphological changes of the corpus callosum in patients with subcortical ischemic vascular dementia. Acta Radiologica. 2015;56(2):214-218. https://doi.org/10.1177/0284185114520863   DOI
15 Lee JY, Oh TH, Yune TY. Ghrelin inhibits hydrogen peroxide-induced apoptotic cell death of oligodendrocytes via ERK and p38MAPK signaling. Endocrinology. 2011;152(6):2377-2386. https://doi.org/10.1210/en.2011-0090   DOI
16 Jantaratnotai N, Ryu JK, Schwab C, McGeer PL, McLarnon JG. Comparison of vascular perturbations in an $A{\beta}$-injected animal model and in AD brain. International Journal of Alzheimer's Disease. 2011;2011:918280. https://doi.org/10.4061/2011/918280   DOI
17 Neto CJBF, Paganelli RA, Benetoli A, Lima KCM, Milani H. Permanent, 3-stage, 4-vessel occlusion as a model of chronic and progressive brain hypoperfusion in rats: A neurohistological and behavioral analysis. Behavioural Brain Research. 2005;160(2):312-322. https://doi.org/10.1016/j.bbr.2004.12.016   DOI
18 Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80(4):844-866. https://doi.org/10.1016/j.neuron.2013.10.008   DOI
19 Kalaria RN. The pathology and pathophysiology of vascular dementia. Neuropharmacology. 2018;134(B):226-239. https://doi.org/10.1016/j.neuropharm.2017.12.030   DOI
20 Ma X, Sun Z, Liu Y, Jia Y, Zhang B, Zhang J. Resveratrol improves cognition and reduces oxidative stress in rats with vascular dementia. Neural Regeneration Research. 2013;8(22):2050-2059. https://doi.org/10.3969/j.issn.1673-5374.2013.22.004
21 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249-257. https://doi.org/10.1038/35025220   DOI
22 Plate KH. Mechanisms of angiogenesis in the brain. Journal of Neuropathology and Experimental Neurology. 1999;58(4):313-320. https://doi.org/10.1097/00005072-199904000-00001   DOI
23 Fan Y, Yang GY. Therapeutic angiogenesis for brain ischemia: A brief review. Journal of Neuroimmune Pharmacology. 2007;2(3):284-289. https://doi.org/10.1007/s11481-007-9073-3   DOI
24 Pillai A, Mahadik SP. Differential effects of haloperidol and olanzapine on levels of vascular endothelial growth factor and angiogenesis in rat hippocampus. Schizophrenia Research. 2006;87(1-3):48-59. https://doi.org/10.1016/j.schres.2006.06.017   DOI
25 Shiojima I, Walsh K. Role of Akt signaling in vascular homeostasis and angiogenesis. Circulation Research. 2002;90(12):1243-1250. https://doi.org/10.1161/01.res.0000022200.71892.9f   DOI
26 Chen J, Cui X, Zacharek A, Cui Y, Roberts C, Chopp M. White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke. Stroke. 2011;42(2):445-452. https://doi.org/10.1161/strokeaha.110.596486   DOI
27 Wang L, Chen Q, Li G, Ke D. Ghrelin stimulates angiogenesis via GHSR1a-dependent MEK/ERK and PI3K/Akt signal pathways in rat cardiac microvascular endothelial cells. Peptides. 2012;33(1):92-100. https://doi.org/10.1016/j.peptides.2011.11.001   DOI
28 Chen X, Chen Q, Wang L, Li G. Ghrelin induces cell migration through GHSR1a-mediated PI3K/Akt/eNOS/NO signaling pathway in endothelial progenitor cells. Metabolism. 2013;62(5):743-752. https://doi.org/10.1016/j.metabol.2012.09.014   DOI
29 Rossi F, Castelli A, Bianco MJ, Bertone C, Brama M, Santiemma V. Ghrelin induces proliferation in human aortic endothelial cells via ERK1/2 and PI3K/Akt activation. Peptides. 2008;29(11):2046-2051. https://doi.org/10.1016/j.peptides.2008.07.002   DOI
30 Candelario-Jalil E, Thompson J, Taheri S, Grossetete M, Adair JC, Edmonds E, et al. Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment. Stroke. 2011;42(5):1345-1350. https://doi.org/10.1161/strokeaha.110.600825   DOI
31 Simpson JE, Fernando MS, Clark L, Ince PG, Matthews F, Forster G, et al. White matter lesions in an unselected cohort of the elderly: Astrocytic, microglial and oligodendrocyte precursor cell responses. Neuropathology and Applied Neurobiology. 2007;33(4):410-419. https://doi.org/10.1111/j.1365-2990.2007.00828.x   DOI
32 Baskys A, Hou AC. Vascular dementia: Pharmacological treatment approaches and perspectives. Clinical Interventions in Aging. 2007;2(3):327-335.
33 Park HR, Park M, Choi J, Park KY, Chung HY, Lee J. A high-fat diet impairs neurogenesis: Involvement of lipid peroxidation and brain-derived neurotrophic factor. Neuroscience Letters. 2010;482(3):235-239. https://doi.org/10.1016/j.neulet.2010.07.046   DOI
34 O'Brien JT, Thomas A. Vascular dementia. The Lancet. 2015;386(10004):1698-1706. https://doi.org/10.1016/S0140-6736(15)00463-8   DOI
35 Jiwa NS, Garrard P, Hainsworth AH. Experimental models of vascular dementia and vascular cognitive impairment: A systematic review. Journal of Neurochemistry. 2010;115(4):814-828. https://doi.org/10.1111/j.1471-4159.2010.06958.x   DOI
36 Olazarán J, Reisberg B, Clare L, Cruz I, Peña-Casanova J, del Ser T, et al. Nonpharmacological therapies in Alzheimer's disease: A systematic review of efficacy. Dementia and Geriatric Cognitive Disorders. 2010;30(2):161-178. https://doi.org/10.1159/000316119   DOI
37 Moon M, Kim S, Hwang L, Park S. Ghrelin regulates hippocampal neurogenesis in adult mice. Endocrine Journal. 2009;56(3):525-531. https://doi.org/10.1507/endocrj.K09E-089   DOI
38 Andrews ZB. The extra-hypothalamic actions of ghrelin on neuronal function. Trends in Neurosciences. 2011;34(1):31-40. https://doi.org/10.1016/j.tins.2010.10.001   DOI
39 Park S. Ghrelin. Endocrinology and Metabolism. 2010; 25(4):258-263. https://doi.org/10.3803/enm.2010.25.4.258   DOI
40 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-660. https://doi.org/10.1038/45230   DOI
41 Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nature Neuroscience. 2006;9(3):381-388. https://doi.org/10.1038/nn1656   DOI
42 Carlini VP, Varas MM, Cragnolini AB, Schiöth HB, Scimonelli TN, de Barioglio SR. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochemical and Biophysical Research Communications. 2004;313(3):635-641. https://doi.org/10.1016/j.bbrc.2003.11.150   DOI
43 Liu Y, Chen L, Xu X, Vicaut E, Sercombe R. Both ischemic preconditioning and ghrelin administration protect hippocampus from ischemia/reperfusion and upregulate uncoupling protein-2. BMC Physiology. 2009;9:17. https://doi.org/10.1186/1472-6793-9-17   DOI
44 Miao Y, Xia Q, Hou Z, Zheng Y, Pan H, Zhu S. Ghrelin protects cortical neuron against focal ischemia/reperfusion in rats. Biochemical and Biophysical Research Communications. 2007;359(3):795-800. https://doi.org/10.1016/j.bbrc.2007.05.192   DOI
45 Liu Y, Wang PS, Xie D, Liu K, Chen L. Ghrelin reduces injury of hippocampal neurons in a rat model of cerebral ischemia/reperfusion. Chinese Journal of Physiology. 2006;49(5):244-250.