The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Ghrelin Protects Spinal Cord Motoneurons Against Chronic Glutamate Excitotoxicity by Inhibiting Microglial Activation

  • Lee, Sung-Youb (Department of Pharmacology and Medical Research Center for Bioreaction to ROS and Biomedical Science Institute, School of Medicine, Kyung Hee University) ;
  • Kim, Yu-Mi (Department of Pharmacology and Medical Research Center for Bioreaction to ROS and Biomedical Science Institute, School of Medicine, Kyung Hee University) ;
  • Li, Endan (Department of Pharmacology and Medical Research Center for Bioreaction to ROS and Biomedical Science Institute, School of Medicine, Kyung Hee University) ;
  • Park, Seung-Joon (Department of Pharmacology and Medical Research Center for Bioreaction to ROS and Biomedical Science Institute, School of Medicine, Kyung Hee University)
  • Received : 2011.12.08
  • Accepted : 2012.01.08
  • Published : 2012.02.29
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Abstract

Glutamate excitotoxicity is emerging as a contributor to degeneration of spinal cord motoneurons in amyotrophic lateral sclerosis (ALS). Recently, we have reported that ghrelin protects motoneurons against chronic glutamate excitotoxicity through the activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-$3{\beta}$ pathways. Previous studies suggest that activated microglia actively participate in the pathogenesis of ALS motoneuron degeneration. However, it is still unknown whether ghrelin exerts its protective effect on motoneurons via inhibition of microglial activation. In this study, we investigate organotypic spinal cord cultures (OSCCs) exposed to threohydroxyaspartate (THA), as a model of excitotoxic motoneuron degeneration, to determine if ghrelin prevents microglial activation. Exposure of OSCCs to THA for 3 weeks produced typical motoneuron death, and treatment of ghrelin significantly attenuated THA-induced motoneuron loss, as previously reported. Ghrelin prevented THA-induced microglial activation in the spinal cord and the expression of pro-inflammatory cytokines tumor necrosis factor-${\alpha}$ and interleukin-$1{\beta}$. Our data indicate that ghrelin may act as a survival factor for motoneurons by functioning as a microglia-deactivating factor and suggest that ghrelin may have therapeutic potential for the treatment of ALS and other neurodegenerative disorders where inflammatory responses play a critical role.

Keywords

References

  1. Goodall EF, Morrison KE. Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment. Expert Rev Mol Med. 2006;8:1-22.
  2. Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W. The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006;1762:1068-1082. https://doi.org/10.1016/j.bbadis.2006.05.002
  3. Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med. 1992;326:1464-1468. https://doi.org/10.1056/NEJM199205283262204
  4. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 1995;38:73-84. https://doi.org/10.1002/ana.410380114
  5. Philips T, Robberecht W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 2011;10:253-263. https://doi.org/10.1016/S1474-4422(11)70015-1
  6. Weydt P, Yuen EC, Ransom BR, Möller T. Increased cytotoxic potential of microglia from ALS-transgenic mice. Glia. 2004;48:179-182. https://doi.org/10.1002/glia.20062
  7. Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, Leigh PN, Banati RB. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15:601-609. https://doi.org/10.1016/j.nbd.2003.12.012
  8. Henkel JS, Beers DR, Zhao W, Appel SH. Microglia in ALS: the good, the bad, and the resting. J Neuroimmune Pharmacol. 2009;4:389-398. https://doi.org/10.1007/s11481-009-9171-5
  9. Lasiene J, Yamanaka K. Glial cells in amyotrophic lateral sclerosis. Neurol Res Int. 2011;2011:718987.
  10. Gonzalez-Scarano F, Baltuch G. Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci. 1999;22:219-240. https://doi.org/10.1146/annurev.neuro.22.1.219
  11. Tikka TM, Vartiainen NE, Goldsteins G, Oja SS, Andersen PM, Marklund SL, Koistinaho J. Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease. Brain. 2002;125:722-731. https://doi.org/10.1093/brain/awf068
  12. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci. 2001;21:2580-2588.
  13. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85:495-522. https://doi.org/10.1152/physrev.00012.2004
  14. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology. 2000;141:4255-4261. https://doi.org/10.1210/en.141.11.4255
  15. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656-660. https://doi.org/10.1038/45230
  16. Peino R, Baldelli R, Rodriguez-Garcia J, Rodriguez-Segade S, Kojima M, Kangawa K, Arvat E, Ghigo E, Dieguez C, Casanueva FF. Ghrelin-induced growth hormone secretion in humans. Eur J Endocrinol. 2000;143:R11-14. https://doi.org/10.1530/eje.0.143R011
  17. 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. 2007;148:148-159.
  18. 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. 2008;198:511-521. https://doi.org/10.1677/JOE-08-0160
  19. Hwang S, Moon M, Kim S, Hwang L, Ahn KJ, Park S. Neuroprotective effect of ghrelin is associated with decreased expression of prostate apoptosis response-4. Endocr J. 2009;56:609-617. https://doi.org/10.1507/endocrj.K09E-072
  20. Moon M, Kim HG, Hwang L, Seo JH, Kim S, Hwang S, Kim S, Lee D, Chung H, Oh MS, Lee KT, Park S. Neuroprotective effect of ghrelin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease by blocking microglial activation. Neurotox Res. 2009;15:332-347. https://doi.org/10.1007/s12640-009-9037-x
  21. Lim E, Lee S, Li E, Kim Y, Park S. Ghrelin protects spinal cord motoneurons against chronic glutamate-induced excitotoxicity via ERK1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-$3{\beta}$ pathways. Exp Neurol. 2011;230:114-122. https://doi.org/10.1016/j.expneurol.2011.04.003
  22. Henkel JS, Engelhardt JI, Siklós L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol. 2004;55:221-235. https://doi.org/10.1002/ana.10805
  23. Lee J, Lim E, Kim Y, Li E, Park S. Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. J Endocrinol. 2010;205:263-270. https://doi.org/10.1677/JOE-10-0040
  24. Llado J, Haenggeli C, Maragakis NJ, Snyder EY, Rothstein JD. Neural stem cells protect against glutamate-induced excitotoxicity and promote survival of injured motor neurons through the secretion of neurotrophic factors. Mol Cell Neurosci. 2004;27: 322-331. https://doi.org/10.1016/j.mcn.2004.07.010
  25. Rothstein JD, Jin L, Dykes-Hoberg M, Kuncl RW. Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity. Proc Natl Acad Sci USA. 1993;90:6591-6595. https://doi.org/10.1073/pnas.90.14.6591
  26. Tolosa L, Caraballo-Miralles V, Olmos G, Llado J. TNF-${\alpha}$ potentiates glutamate-induced spinal cord motoneuron death via NF-${\kappa}$B. Mol Cell Neurosci. 2011;46:176-186. https://doi.org/10.1016/j.mcn.2010.09.001
  27. Lee JY, Chung H, Yoo YS, Oh YJ, Oh TH, Park S, Yune TY. Inhibition of apoptotic cell death by ghrelin improves functional recovery after spinal cord injury. Endocrinology. 2010;151:3815-3826. https://doi.org/10.1210/en.2009-1416
  28. del Rio-Hortega P. Art and artifice in the science of histology. 1933. Histopathology. 1993;22:515-525. https://doi.org/10.1111/j.1365-2559.1993.tb00171.x
  29. 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. 2009;30:2286-2291. https://doi.org/10.1016/j.peptides.2009.09.004
  30. Chow KB, Cheng CH, Wise H. Anti-inflammatory activity of ghrelin in human carotid artery cells. Inflammation. 2009;32:402-409. https://doi.org/10.1007/s10753-009-9149-8
  31. Theil MM, Miyake S, Mizuno M, Tomi C, Croxford JL, Hosoda H, Theil J, von Hörsten S, Yokote H, Chiba A, Lin Y, Oki S, Akamizu T, Kangawa K, Yamamura T. Suppression of experimental autoimmune encephalomyelitis by ghrelin. J Immunol. 2009;183:2859-2866. https://doi.org/10.4049/jimmunol.0803362
  32. Ersahin M, Toklu HZ, Erzik C, Cetinel S, Akakin D, Velioglu-Ogunc A, Tetik S, Ozdemir ZN, Sener G, Yegen BC. The anti-inflammatory and neuroprotective effects of ghrelin in subarachnoid hemorrhage-induced oxidative brain damage in rats. J Neurotrauma. 2010;27:1143-1155. https://doi.org/10.1089/neu.2009.1210
  33. Andrews ZB, Erion D, Beiler R, Liu ZW, Abizaid A, Zigman J, Elsworth JD, Savitt JM, DiMarchi R, Tschoep M, Roth RH, Gao XB, Horvath TL. Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J Neurosci. 2009;29:14057-14065. https://doi.org/10.1523/JNEUROSCI.3890-09.2009
  34. Jiang H, Li LJ, Wang J, Xie JX. Ghrelin antagonizes MPTPinduced neurotoxicity to the dopaminergic neurons in mouse substantia nigra. Exp Neurol. 2008;212:532-537. https://doi.org/10.1016/j.expneurol.2008.05.006
  35. Obay BD, Tasdemir E, Tümer C, Bilgin HM, Sermet A. Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats. Peptides. 2007;28:1214-1219. https://doi.org/10.1016/j.peptides.2007.04.003

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