Skip to main content
SpringerLink
Log in
Book cover

Central Functions of the Ghrelin Receptor pp 177–189Cite as

Ghrelin Receptors and Epilepsy

  • Chapter
  • First Online:

Part of the book series: The Receptors ((REC,volume 25))

Abstract

Epilepsy is a neurological disorder that affects more than 50 million people worldwide. One-third of all epilepsy patients do not respond to the antiepileptic medications that are currently available. As such, there is a great need for new, more effective drugs for the treatment of epilepsy. Drugs that target neuropeptide systems in the brain show great promise for preventing seizures and epilepsy. Little is currently known about the ghrelin receptor and its role in epilepsy. In this chapter, we discuss whether the ghrelin system is a promising target to stop seizures or prevent the development of epilepsy. This is done by looking at what is currently known, as well as what physiological functions of the ghrelin receptor may be beneficial in epilepsy. The final part of this chapter highlights a number of factors that need to be investigated to understand better the function of the ghrelin receptor in epileptic states. These suggestions may indirectly give an insight to researchers studying ghrelin in other fields of research.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Angelidis G, Valotassiou V, Georgoulias P (2010) Current and potential roles of ghrelin in clinical practice. J Endocrinol Invest 33:823–838

    Article  CAS  PubMed  Google Scholar 

  • Aslan A, Yildirim M, Ayyildiz M, Guven A, Agar E (2009) The role of nitric oxide in the inhibitory effect of ghrelin against penicillin-induced epileptiform activity in rat. Neuropeptides 43:295–302

    Article  CAS  PubMed  Google Scholar 

  • Ataie Z, Golzar MG, Babri S, Ebrahimi H, Mohaddes G (2011) Does ghrelin level change after epileptic seizure in rats? Seizure 20:347–349

    Article  CAS  PubMed  Google Scholar 

  • Baatar D, Patel K, Taub DD (2011) The effects of ghrelin on inflammation and the immune system. Mol Cell Endocrinol 340:44–58

    Article  CAS  PubMed  Google Scholar 

  • Beck H, Goussakov IV, Lie A, Helmstaedter C, Elger CE (2000) Synaptic plasticity in the human dentate gyrus. J Neurosci 20:7080–7086

    CAS  PubMed  Google Scholar 

  • Biagini G, Torsello A, Marinelli C, Gualtieri F, Vezzali R, Coco S, Bresciani E, Locatelli V (2011) Beneficial effects of desacyl-ghrelin, hexarelin and EP-80317 in models of status epilepticus. Eur J Pharmacol 670:130–136

    Article  CAS  PubMed  Google Scholar 

  • Bialer M, White HS (2010) Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 9:68–82

    Article  CAS  PubMed  Google Scholar 

  • Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39

    Article  CAS  PubMed  Google Scholar 

  • Boer K, Jansen F, Nellist M, Redeker S, van den Ouweland AM, Spliet WG, van Nieuwenhuizen O, Troost D, Crino PB, Aronica E (2008) Inflammatory processes in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Epilepsy Res 78:7–21

    Article  CAS  PubMed  Google Scholar 

  • Cheyuo C, Wu R, Zhou M, Jacob A, Coppa G, Wang P (2011) Ghrelin suppresses inflammation and neuronal nitric oxide synthase in focal cerebral ischemia via the vagus nerve. Shock 35:258–265

    Article  CAS  PubMed  Google Scholar 

  • Choi J, Koh S (2008) Role of brain inflammation in epileptogenesis. Yonsei Med J 49:1–18

    Article  PubMed Central  PubMed  Google Scholar 

  • Chu KM, Chow KB, Leung PK, Lau PN, Chan CB, Cheng CH, Wise H (2007) Over-expression of the truncated ghrelin receptor polypeptide attenuates the constitutive activation of phosphatidylinositol-specific phospholipase C by ghrelin receptors but has no effect on ghrelin-stimulated extracellular signal-regulated kinase 1/2 activity. Int J Biochem Cell Biol 39:752–764

    Article  CAS  PubMed  Google Scholar 

  • Chung H, Seo S, Moon M, Park S (2008) 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

    Article  CAS  PubMed  Google Scholar 

  • Chung H, Li E, Kim Y, Kim S, Park S (2013) Multiple signaling pathways mediate ghrelin-induced proliferation of hippocampal neural stem cells. J Endocrinol 218(1):49–59

    Google Scholar 

  • Clinckers R, Smolders I, Meurs A, Ebinger G, Michotte Y (2004) Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5-HT receptors. J Neurochem 89:834–843

    Article  CAS  PubMed  Google Scholar 

  • Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649–661

    Article  CAS  PubMed  Google Scholar 

  • Delhanty PJ, van Koetsveld PM, Gauna C, van de Zande B, Vitale G, Hofland LJ, van der Lely AJ (2007) Ghrelin and its unacylated isoform stimulate the growth of adrenocortical tumor cells via an anti-apoptotic pathway. Am J Physiol Endocrinol Metab 293:E302–E309

    Article  CAS  PubMed  Google Scholar 

  • Dello Russo C, Lisi L, Tringali G, Navarra P (2009) Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol 78:1242–1251

    Google Scholar 

  • Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschop MH, Horvath TL (2006) Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 9:381–388

    Article  CAS  PubMed  Google Scholar 

  • Fattore C, Perucca E (2011) Novel medications for epilepsy. Drugs 71:2151–2178

    Article  CAS  PubMed  Google Scholar 

  • Ferrini F, Salio C, Lossi L, Merighi A (2009) Ghrelin in central neurons. Curr Neuropharmacol 7:37–49

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gangarossa G, Di Benedetto M, O’Sullivan GJ, Dunleavy M, Alcacer C, Bonito-Oliva A, Henshall DC, Waddington JL, Valjent E, Fisone G (2011) Convulsant doses of a dopamine D1 receptor agonist result in Erk-dependent increases in Zif268 and Arc/Arg3.1 expression in mouse dentate gyrus. PLoS ONE 6:e19415

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Granata R, Settanni F, Biancone L, Trovato L, Nano R, Bertuzzi F, Destefanis S, Annunziata M, Martinetti M, Catapano F, Ghe C, Isgaard J, Papotti M, Ghigo E, Muccioli G (2007) Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3′,5′-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling. Endocrinology 148:512–529

    Article  CAS  PubMed  Google Scholar 

  • Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW (2003) High constitutive signaling of the ghrelin receptor–identification of a potent inverse agonist. Mol Endocrinol 17:2201–2210

    Article  CAS  PubMed  Google Scholar 

  • Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA (2006) Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward. Addict Biol 11:45–54

    Article  CAS  PubMed  Google Scholar 

  • Jiang H, Betancourt L, Smith RG (2006) Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Mol Endocrinol 20:1772–1785

    Article  CAS  PubMed  Google Scholar 

  • Kebabian JW, Greengard P (1971) Dopamine-sensitive adenyl cyclase: possible role in synaptic transmission. Science 174:1346–1349

    Article  CAS  PubMed  Google Scholar 

  • Kern A, Albarran-Zeckler R, Walsh HE, Smith RG (2012) Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron 73:317–332

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee J, Lim E, Kim Y, Li E, Park S (2010) Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. J Endocrinol 205:263–270

    Article  CAS  PubMed  Google Scholar 

  • Leung PK, Chow KB, Lau PN, Chu KM, Chan CB, Cheng CH, Wise H (2007) The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant-negative mutant of the ghrelin receptor. Cell Signal 19:1011–1022

    Article  CAS  PubMed  Google Scholar 

  • Li E, Chung H, Kim Y, Kim DH, Ryu JH, Sato T, Kojima M, Park S (2013) Ghrelin directly stimulates adult hippocampal neurogenesis: implications for learning and memory. Endocr J 60(6):781–789

    Google Scholar 

  • Librizzi L, Noe F, Vezzani A, de Curtis M, Ravizza T (2012) Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann Neurol 72:82–90

    Article  PubMed  Google Scholar 

  • Lopez NE, Krzyzaniak MJ, Blow C, Putnam J, Ortiz-Pomales Y, Hageny AM, Eliceiri B, Coimbra R, Bansal V (2011) Ghrelin prevents disruption of the Blood-Brain Barrier after traumatic Brain injury. J Neurotrauma

    Google Scholar 

  • Lopez NE, Gaston L, Lopez KR, Coimbra RC, Hageny A, Putnam J, Eliceiri B, Coimbra R, Bansal V (2012) Early ghrelin treatment attenuates disruption of the blood brain barrier and apoptosis after traumatic brain injury through a UCP-2 mechanism. Brain Res 1489:140–148

    Article  CAS  PubMed  Google Scholar 

  • Marchi N, Granata T, Ghosh C, Janigro D (2012) Blood-brain barrier dysfunction and epilepsy: pathophysiologic role and therapeutic approaches. Epilepsia 53:1877–1886

    Article  PubMed  Google Scholar 

  • Martins L, Fernandez-Mallo D, Novelle MG, Vazquez MJ, Tena-Sempere M, Nogueiras R, Lopez M, Dieguez C (2012) Hypothalamic mTOR signaling mediates the orexigenic action of ghrelin. PLoS ONE 7:e46923

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mary S, Fehrentz JA, Damian M, Gaibelet G, Orcel H, Verdie P, Mouillac B, Martinez J, Marie J, Baneres JL (2013) Heterodimerization with Its splice variant blocks the ghrelin receptor 1a in a non-signaling conformation: a study with a purified heterodimer assembled into lipid discs. J Biol Chem 288:24656–24665

    Article  CAS  PubMed  Google Scholar 

  • Moon M, Kim S, Hwang L, Park S (2009) Ghrelin regulates hippocampal neurogenesis in adult mice. Endocr J 56:525–531

    Article  CAS  PubMed  Google Scholar 

  • Obay BD, Tasdemir E, Tumer C, Bilgin HM, Sermet A (2007) Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats. Peptides 28:1214–1219

    Article  CAS  PubMed  Google Scholar 

  • Obay BD, Tasdemir E, Tumer C, Bilgin H, Atmaca M (2008a) Dose dependent effects of ghrelin on pentylenetetrazole-induced oxidative stress in a rat seizure model. Peptides 29:448–455

    Article  CAS  PubMed  Google Scholar 

  • Obay BD, Tasdemir E, Tumer C, Bilgin HM, Atmaca M (2008b) Dose dependent effects of ghrelin on pentylenetetrazole-induced oxidative stress in a rat seizure model. Peptides 29:448–455

    Article  CAS  PubMed  Google Scholar 

  • O’Sullivan GJ, Dunleavy M, Hakansson K, Clementi M, Kinsella A, Croke DT, Drago J, Fienberg AA, Greengard P, Sibley DR, Fisone G, Henshall DC, Waddington JL (2008) Dopamine D1 versus D5 receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling. Neuropharmacology 54:1051–1061

    Article  PubMed Central  PubMed  Google Scholar 

  • Parent JM, Kron MM (2012) Neurogenesis and epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies [Internet], 4th edn. National Center for Biotechnology Information, Bethesda

    Google Scholar 

  • Pitkanen A, Lukasiuk K (2011) Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 10:173–186

    Article  PubMed  Google Scholar 

  • Portelli J, Michotte Y, Smolders I (2012a) Ghrelin: an emerging new anticonvulsant neuropeptide. Epilepsia 53:585–595

    Article  CAS  PubMed  Google Scholar 

  • Portelli J, Thielemans L, Ver Donck L, Loyens E, Coppens J, Aourz N, Aerssens J, Vermoesen K, Clinckers R, Schallier A, Michotte Y, Moechars D, Collingridge GL, Bortolotto ZA, Smolders I (2012b) Inactivation of the constitutively active ghrelin receptor attenuates limbic seizure activity in rodents. Neurotherapeutics 9:658–672

    Google Scholar 

  • Prunetti P, Perucca E (2011) New and forthcoming anti-epileptic drugs. Curr Opin Neurol 24:159–164

    Article  CAS  PubMed  Google Scholar 

  • Ravizza T, Boer K, Redeker S, Spliet WG, van Rijen PC, Troost D, Vezzani A, Aronica E (2006) The IL-1beta system in epilepsy-associated malformations of cortical development. Neurobiol Dis 24:128–143

    Article  CAS  PubMed  Google Scholar 

  • Ravizza T, Gagliardi B, Noe F, Boer K, Aronica E, Vezzani A (2008) Innate and adaptive immunity during epileptogenesis and spontaneous seizures: evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis 29:142–160

    Article  CAS  PubMed  Google Scholar 

  • Rediger A, Piechowski CL, Yi CX, Tarnow P, Strotmann R, Gruters A, Krude H, Schoneberg T, Tschop MH, Kleinau G, Biebermann H (2011) Mutually opposite signal modulation by hypothalamic heterodimerization of ghrelin and melanocortin-3 receptors. J Biol Chem 286:39623–39631

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rogawski MA (2006a) Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 69:273–294

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rogawski MA (2006b) Molecular targets versus models for new antiepileptic drug discovery. Epilepsy Res 68:22–28

    Article  PubMed Central  PubMed  Google Scholar 

  • Russo E, Citraro R, Constanti A, De Sarro G (2012) The mTOR signaling pathway in the brain: focus on epilepsy and epileptogenesis. Mol Neurobiol 46:662–681

    Article  CAS  PubMed  Google Scholar 

  • Russo E, Citraro R, Donato G, Camastra C, Iuliano R, Cuzzocrea S, Constanti A, De Sarro G (2013) mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy. Neuropharmacology 69:25–36

    Google Scholar 

  • Scharfman HE (2007) The neurobiology of epilepsy. Curr Neurol Neurosci Rep 7:348–354

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Starr MS (1996) The role of dopamine in epilepsy. Synapse 22:159–194

    Article  CAS  PubMed  Google Scholar 

  • Starr MS, Starr BS (1993) Seizure promotion by D1 agonists does not correlate with other dopaminergic properties. J Neural Transm Park Dis Dement Sect 6:27–34

    Article  CAS  PubMed  Google Scholar 

  • Stevanovic D, Starcevic V, Vilimanovich U, Nesic D, Vucicevic L, Misirkic M, Janjetovic K, Savic E, Popadic D, Sudar E, Micic D, Sumarac-Dumanovic M, Trajkovic V (2011) Immunomodulatory actions of central ghrelin in diet-induced energy imbalance. Brain Behav Immun 26:150–158

    Article  PubMed  Google Scholar 

  • Trantham-Davidson H, Neely LC, Lavin A, Seamans JK (2004) Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci 24:10652–10659

    Article  CAS  PubMed  Google Scholar 

  • Vliet EA van, Costa Araujo S da, Redeker S, Schaik R van, Aronica E, Gorter JA (2007) Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130:521–534

    Google Scholar 

  • Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31–40

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24

    Google Scholar 

  • Vliet EA van, Forte G, Holtman L, Burger JC den, Sinjewel A, Vries HE de, Aronica E, Gorter JA. Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia, 2012; 53: 1254-63

    Google Scholar 

  • World Health Organization (2009) Epilepsy in the WHO European region. http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf

  • Xu J, Wang S, Lin Y, Cao L, Wang R, Chi Z (2009) Ghrelin protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. Neurosci Lett 453:58–61

    Article  CAS  PubMed  Google Scholar 

  • Zhang R, Yang G, Wang Q, Guo F, Wang H (2013) Acylated ghrelin protects hippocampal neurons in pilocarpine-induced seizures of immature rats by inhibiting cell apoptosis. Mol Biol Rep 40:51–58

    Article  PubMed  Google Scholar 

  • Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Center for Neurosciences, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium

    Jeanelle Portelli, Ann Massie, Jessica Coppens & Ilse Smolders

  2. Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Institute for Neuroscience, Ghent University Hospital, De Pintelaan 185, 1K12A, 9000, Gent, Belgium

    Jeanelle Portelli

Authors
  1. Jeanelle Portelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ann Massie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jessica Coppens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilse Smolders
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ilse Smolders .

Editor information

Editors and Affiliations

  1. Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium

    Jeanelle Portelli

  2. Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium

    Ilse Smolders

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Portelli, J., Massie, A., Coppens, J., Smolders, I. (2014). Ghrelin Receptors and Epilepsy. In: Portelli, J., Smolders, I. (eds) Central Functions of the Ghrelin Receptor. The Receptors, vol 25. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0823-3_11

Download citation

Publish with us

Policies and ethics

Search

Navigation