Administration of ghrelin associated with decreased expression of matrix metalloproteinase-9 following normobaric systemic hypoxia in the brain

Mohaddes, Gisou; Babri, Shirin; Hossienzadeh, Fezzeh

doi:10.2478/enr-2018-0019

Abstract

Objective. According to our previous studies, ghrelin protects blood brain barrier (BBB) integrity and it attenuates hypoxia-induced brain edema in the hypoxic conditions. However, the underlying mechanisms remain poorly understood. Several studies suggest a role for matrix metal-loproteinase-9 (MMP9) in the BBB disruption and cerebral edema formation. The present study was conducted to determine the effect of ghrelin on MMP9 protein expression in the model of acute and chronic systemic hypoxia.

Methods. Adult male Wistar rats were divided into acute or chronic controls, acute or chronic hypoxia and ghrelin-treated acute or chronic hypoxia groups. The hypoxic groups were kept in the hypoxic chamber (10–11% O₂) for two (acute) or ten days (chronic). Effect of ghrelin on MMP9 protein expression was assessed using immunoblotting.

Results. Our results showed that acute and chronic systemic hypoxia increased the MMP9 protein expression in the brain (p<0.001). Treatment with ghrelin significantly attenuated this expression in the cerebral hypoxia (p<0.05).

Conclusion. Our results demonstrate that the neuroprotective effects of ghrelin may be mediated, in part, by decreasing in MMP9 production in the hypoxic brain.

References

Andrews ZB. The extra-hypothalamic actions of ghrelin on neuronal function. Trends Neurosci 34, 31–40, 2011.10.1016/j.tins.2010.10.00121035199
Open DOI Search in Google Scholar Back to article
Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci 21, 7724–7732, 2001.10.1523/JNEUROSCI.21-19-07724.2001
Open DOI Search in Google Scholar Back to article
Babri S, Mohaddes G, Alipour MR, Ebrahimi H, Hossenzadeh F. Effects of ghrelin on plasma glucose levels, body weight, food intake and hematocrit in acute and chronic systemic hypoxia in adult male rats. Iran J Endocrinol Metab 15, 100–106, 2013.
Search in Google Scholar Back to article
Bansal V. Ryu SY, Blow C, Costantini T, Loomis W, Elicerri B, Baird A, Wolf P, Coimbra R. The hormone ghrelin prevents traumatic brain injury induced intestinal dysfunction. J Neurotrauma 27, 2255–2260, 2010.10.1089/neu.2010.1372
Open DOI Search in Google Scholar Back to article
Bauer AT, Burgers HF, Rabie T, Marti HH. Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. J Cereb Blood Flow Metab 30, 837–848, 2010.10.1038/jcbfm.2009.248
Search in Google Scholar Back to article
Belotti D, Paganoni P, Manenti L, Garofalo A, Marchini S, Taraboletti G, Giavazzi R. Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: implications for ascites formation. Cancer Res 63, 5224–5229, 2003.
Search in Google Scholar Back to article
Bond M, Chase A, Baker AH, Newby AC. Inhibition of transcription factor NF-κB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells. Cardiovasc Res 50, 556–565, 2001.10.1016/S0008-6363(01)00220-6
Search in Google Scholar Back to article
Brywe KG, Leverin AL, Gustavsson M, Mallard C, Granata R, Destefanis S, Volante M, Hagberg H, Ghigo E, Isgaard J. Growth hormone-releasing peptide hexarelin reduces neonatal brain injury and alters Akt/glycogen synthase kinase-3 beta phosphorylation. Endocrinology 146, 4665–4672, 2005.10.1210/en.2005-0389
Search in Google Scholar Back to article
Carlini VP, Monzon ME, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR. Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun 299, 739–743, 2002.10.1016/S0006-291X(02)02740-7
Search in Google Scholar Back to article
Cheyuo C, Wu R, Zhou M, Jacob A, Coppa G, Wang P. Ghrelin suppresses inflammation and neuronal nitric oxide synthase in focal cerebral ischemia via the vagus nerve. Shock 35, 258–265, 2011.2072051210.1097/SHK.0b013e3181f48a3720720512
Open DOI Search in Google Scholar Back to article
Chung H, Kim E, Lee DH, Seo S, Ju S, Lee D, Kim H, Park S. Ghrelin inhibits apoptosis in hypothalamic neuronal cells during oxygen-glucose deprivation. Endocrinology 148, 148–159, 2007.10.1210/en.2006-09911705302417053024
Open DOI Search in Google Scholar Back to article
Chung H, Seo S, Moon M, Park S. Phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. J Endocrinol 198, 511–521, 2008.10.1677/JOE-08-016018541646
Search in Google Scholar Back to article
Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50, 329–339, 2005.1584680210.1002/glia.2016915846802
Open DOI Search in Google Scholar Back to article
Diano S, Farr SS, Benoit SC, McNay EC, Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks MA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschop MH, Horvath TL. Ghrelin controls hippo-campal spine synapse density and memory performance. Nat Neurosci 9, 381–388, 2006.10.1038/nn165616491079
Open DOI Search in Google Scholar Back to article
Duansak N, Schmid-Schonbein GW. The oxygen free radicals control MMP-9 and transcription factors expression in the spontaneously hypertensive rat. Microvasc Res 90, 154–161, 2013.10.1016/j.mvr.2013.09.00324060804464299824060804
Open DOI Search in Google Scholar Back to article
Duran-Vilaregut J, del Valle J, Manich G, Camins A, Pallas M, Vilaplana J, Pelegri C. Role of matrix metalloproteinase-9 (MMP-9) in striatal blood-brain barrier disruption in a 3-nitropropionic acid model of Huntington’s disease. Neuropathol Appl Neurobiol 37, 525–537, 2011.10.1111/j.1365-2990.2010.01157.x21175737
Search in Google Scholar Back to article
Ersahin M, Toklu HZ, Erzik C, Cetinel S, Akakin D, Velioglu-Ogunc A, Tetik S, Ozdemir ZN, Sener G, Yegen BC. The antiinflammatory and neuroprotective effects of ghrelin in subarachnoid hemorrhage-induced oxidative brain damage in rats. J Neurotrauma 27, 1143–1155, 2010.10.1089/neu.2009.121020205513
Open DOI Search in Google Scholar Back to article
Feizi H, Rajaee K, Keyhanmanesh R, Aliparasti MR, Almasi S, Alipour MR. Effect of ghrelin on renal erythropoietin production in chronic hypoxic rats. Endocr Regul 48, 3–8, 2014.2452437010.4149/endo_2014_01_324524370
Search in Google Scholar Back to article
Fry M, Ferguson AV. Ghrelin: central nervous system sites of action in regulation of energy balance. Int J Pept 2010, 2010.10.1155/2010/616757292508220798749
Search in Google Scholar Back to article
Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab 21, 1393–1400, 2001.10.1097/00004647-200112000-0000311740200
Search in Google Scholar Back to article
Hossienzadeh F, Babri S, Alipour MR, Ebrahimi H, Mohaddes G. Effect of ghrelin on brain edema induced by acute and chronic systemic hypoxia. Neurosci Lett 534, 47–51, 2013.10.1016/j.neulet.2012.11.06223295905
Search in Google Scholar Back to article
Higashida T, Kreipke CW, Rafols JA, Peng C, Schafer S, Schafer P, Ding JY, Dornbos D 3rd, Li X, Guthikonda M, Rossi NF, Ding Y. The role of hypoxia-inducible factor-1α, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury. J Neurosurg 114, 92–101, 2011.10.3171/2010.6.JNS1020720617879
Open DOI Search in Google Scholar Back to article
Huang CX, Yuan MJ, Huang H, Wu G, Liu Y, Yu SB, Li HT, Wang T. Ghrelin inhibits post-infarct myocardial remodeling and improves cardiac function through anti-inflammation effect. Peptides 30, 2286–2291, 2009.10.1016/j.peptides.2009.09.00419747956
Open DOI Search in Google Scholar Back to article
Kheradmand A, Alirezaei M, Birjandi M. Ghrelin promotes antioxidant enzyme activity and reduces lipid peroxidation in the rat ovary. Regul Pept 162, 84–89, 2010.10.1016/j.regpep.2010.02.008
Search in Google Scholar Back to article
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660, 1999.10.1038/45230
Search in Google Scholar Back to article
Lee JY, Choi HY, Na WH, Ju BG, Yune TY. Ghrelin inhibits BSCB disruption/hemorrhage by attenuating MMP-9 and SUR1/TrpM4 expression and activation after spinal cord injury. Biochim Biophys Acta 1842, 2403–2412, 2014.10.1016/j.bbadis.2014.09.006
Search in Google Scholar Back to article
Liu Y, Wang PS, Xie D, Liu K, Chen L. Ghrelin reduces injury of hippocampal neurons in a rat model of cerebral ischemia/reperfusion. Chin J Physiol 49, 244–250, 2006.
Search in Google Scholar Back to article
Miao Y, Xia Q, Hou Z, Zheng Y, Pan H, Zhu S. Ghrelin protects cortical neuron against focal ischemia/reperfusion in rats. Biochem Biophys Res Commun 359, 795–800, 2007.10.1016/j.bbrc.2007.05.192
Search in Google Scholar Back to article
Mohaddes G, Abdolalizadeh J, Babri S, Abedini N, Hossienzadeh F. The anti-edematous effect of ghrelin in brain hypoxia is associated with decreasing expression of vascular endothelial growth factor. J Mol Neurosci 56, 273–277, 2015.2572578610.1007/s12031-015-0528-3
Search in Google Scholar Back to article
Mohaddes G, Abdolalizadeh J, Babri S, Hossienzadeh F. Ghrelin ameliorates blood-brain barrier disruption during systemic hypoxia. Exp Physiol 102, 376–382, 2017.10.1113/EP086068
Open DOI Search in Google Scholar Back to article
Park SL, Won SY, Song JH, Kambe T, Nagao M, Kim WJ, Moona SK. EPO gene expression promotes proliferation, migration and invasion via the p38MAPK/AP-1/MMP-9 pathway by p21WAF1 expression in vascular smooth muscle cells. Cell Signal 27, 470–478, 2015.10.1016/j.cellsig.2014.12.001
Search in Google Scholar Back to article
Reszec J, Hermanowicz A, Rutkowski R, Turek G, Mariak Z, Chyczewski L. Expression of MMP-9 and VEGF in meningiomas and their correlation with peritumoral brain edema. Biomed Res Int 2015, 2015.10.1155/2015/646853
Search in Google Scholar Back to article
Rosenberg GA. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol 8, 205–216, 2009.10.1016/S1474-4422(09)70016-X
Search in Google Scholar Back to article
Sato T, Ito A, Ogata Y, Nagase H, Mori Y. Tumor necrosis factor alpha (TNFalpha) induces pro-matrix metalloproteinase 9 production in human uterine cervical fibroblasts but interleukin 1alpha antagonizes the inductive effect of TNF alpha. FEBS Lett 392, 175–178, 1996.10.1016/0014-5793(96)00808-3
Search in Google Scholar Back to article
Sifringer M, Genz K, Brait D, Brehmer F, Lober R, Weichelt U, Kaindl AM, Gerstner B, Felderhoff-Mueser U. Erythropoietin attenuates hyperoxia-induced cell death by modulation of inflammatory mediators and matrix metalloproteinases. Dev Neurosci 31, 394–402, 2009.10.1159/000232557
Search in Google Scholar Back to article
Vecil GG, Larsen PH, Corley SM, Herx LM, Besson A, Goodyer CG, Yong VW. Interleukin-1 is a key regulator of matrix metalloproteinase-9 expression in human neurons in culture and following mouse brain trauma in vivo. J Neurosci Res 61, 212–224, 2000.10.1002/1097-4547(20000715)61:2<;212::AID-JNR12>3.0.CO;2-9
Search in Google Scholar Back to article
Wang H, Keiser JA. Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: role of flt-1. Circ Res 83, 832–840, 1998.10.1161/01.RES.83.8.832
Search in Google Scholar Back to article
Wang X, Jung J, Asahi M, Chwang W, Russo L, Moskowitz MA, Dixon CE, Fini ME, Lo EH. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci 20, 7037–7042, 2000.10.1523/JNEUROSCI.20-18-07037.2000
Open DOI Search in Google Scholar Back to article
Wu H, Dong G, Liu H, Xu B, Li D, Jing H. Erythropoietin attenuates ischemia-reperfusion induced lung injury by inhibiting tumor necrosis factor-alpha and matrix metalloproteinase-9 expression. Eur J Pharmacol 602, 406–412, 2009.10.1016/j.ejphar.2008.11.037
Search in Google Scholar Back to article
Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27, 697–709, 2007.10.1038/sj.jcbfm.9600375
Search in Google Scholar Back to article
Zhang Q, Huang C, Meng B, Tang T, Shi Q, Yang H. Acute effect of ghrelin on ischemia/reperfusion injury in the rat spinal cord. Int J Mol Sci 13, 9864–9876, 2012.10.3390/ijms1308986422949835
Open DOI Search in Google Scholar Back to article
Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK. Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 494, 528–548, 2006.10.1002/cne.20823
Search in Google Scholar Back to article

Administration of ghrelin associated with decreased expression of matrix metalloproteinase-9 following normobaric systemic hypoxia in the brain

Abstract

Paradigm

My account