Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

Neurotherapeutics

Volumn 9, Issue 3, 2012, Pages 658-672

  Portelli, Jeanelle ^a   Thielemans, Leen ^b   Ver Donck, Luc ^b   Loyens, Ellen ^a   Coppens, Jessica ^a   Aourz, Najat ^a   Aerssens, Jeroen ^b   Vermoesen, Katia ^a   Clinckers, Ralph ^a   Schallier, Anneleen ^a   Michotte, Yvette ^a   Moechars, Dieder ^b   Collingridge, Graham L ^c,d   Bortolotto, Zuner A ^c   Smolders, Ilse ^a  

^a VRIJE UNIVERSITEIT BRUSSEL   (Belgium)

^b JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

^c UNIVERSITY OF BRISTOL   (United Kingdom)

^d Seoul National University   (South Korea)

Author keywords

Epilepsy; Ghrelin; GHSR; Hippocampus; Pilocarpine; Seizures

Indexed keywords

A 778193; CAPROMORELIN; GHRELIN; GHRELIN RECEPTOR; GHRELIN RECEPTOR ANTAGONIST; GROWTH HORMONE SECRETAGOGUE RECEPTOR; PILOCARPINE; RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTICONVULSANT ACTIVITY; ARTICLE; BRAIN SLICE; COMPLEX PARTIAL SEIZURE; CONTROLLED STUDY; DISEASE PREDISPOSITION; DRUG MECHANISM; DRUG TARGETING; EPILEPSY; EPILEPTIC DISCHARGE; HIPPOCAMPUS; HORMONE ACTION; HUMAN; HUMAN CELL; INTERNALIZATION; KNOCKOUT MOUSE; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; RAT; RECEPTOR BLOCKING; RECEPTOR DOWN REGULATION; SEIZURE THRESHOLD; WILD TYPE;

ANALYSIS OF VARIANCE; ANIMALS; ANTICONVULSANTS; CALCIUM; DISEASE MODELS, ANIMAL; DISEASE SUSCEPTIBILITY; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG INTERACTIONS; ELECTRIC STIMULATION; EXCITATORY POSTSYNAPTIC POTENTIALS; GAMMA-AMINOBUTYRIC ACID; GHRELIN; GREEN FLUORESCENT PROTEINS; HEK293 CELLS; HIPPOCAMPUS; HUMANS; LIMBIC SYSTEM; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MICRODIALYSIS; MUSCARINIC AGONISTS; NEURONS; PATCH-CLAMP TECHNIQUES; PILOCARPINE; PIPERIDINES; PYRAZOLES; RATS; RATS, WISTAR; RECEPTORS, GHRELIN; SEIZURES; SEVERITY OF ILLNESS INDEX; SPECIES SPECIFICITY; TRANSFECTION;

EID: 84866468550     PISSN: 19337213     EISSN: 18787479     Source Type: Journal    
DOI: 10.1007/s13311-012-0125-x     Document Type: Article

References (66)

1. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656-660.
2. Diano S, Farr SA, Benoit SC, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 2006; 9: 381-388.
3. Andrews ZB, Liu ZW, Wallingford N, et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 2008; 454: 846-851.
4. Angelidis G, Valotassiou V, Georgoulias P. Current and potential roles of ghrelin in clinical practice. J Endocrinol Invest 2010; 33: 823-838.
5. Camina JP. Cell biology of the ghrelin receptor. J Neuroendocrinol 2006; 18: 65-76.
6. Thielemans L, Peeters PJ, Jonckheere H, et al. The hepatocarcinoma cell line HepG2 does not express a GHS-R1a-type ghrelin receptor. J Recept Signal Transduct Res 2007; 27: 309-322.
7. Chen L, Xing T, Wang M, 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. Eur J Neurosci 2011; 33: 266-275.
8. Davis JF, Choi DL, Clegg DJ, Benoit SC. Signaling through the ghrelin receptor modulates hippocampal function and meal anticipation in mice. Physiol Behav 2011; 103: 39-43.
9. Andrews ZB. The extra-hypothalamic actions of ghrelin on neuronal function. Trends Neurosci 2011; 34: 31-40.
10. 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.
11. Xu J, Wang S, Lin Y et al. Ghrelin protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats. Neurosci Lett 2009; 453: 58-61.
12. Pitkanen A, Lukasiuk K. Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 2011; 10: 173-186.
13. Rogawski MA. Molecular targets versus models for new antiepileptic drug discovery. Epilepsy Res 2006; 68: 22-28.
14. Robertson CR, Flynn SP, White HS, Bulaj G. Anticonvulsant neuropeptides as drug leads for neurological diseases. Nat Prod Rep 2011; 28: 741-762.
15. Berilgen MS, Mungen B, Ustundag B, Demir C. Serum ghrelin levels are enhanced in patients with epilepsy. Seizure 2006; 15: 106-111.
16. Gungor S, Yucel G, Akinci A, et al. The role of ghrelin in weight gain and growth in epileptic children using valproate. J Child Neurol 2007; 22: 1384-1388.
17. Aydin S, Dag E, Ozkan Y, et al. Time-dependent changes in the serum levels of prolactin, nesfatin-1 and ghrelin as a marker of epileptic attacks young male patients. Peptides 2011; 32: 1276-1280.
18. Greco R, Latini G, Chiarelli F, Iannetti P, Verrotti A. Leptin, ghrelin, and adiponectin in epileptic patients treated with valproic acid. Neurology 2005; 65: 1808-1809.
19. Aydin S, Dag E, Ozkan Y, et al. Nesfatin-1 and ghrelin levels in serum and saliva of epileptic patients: hormonal changes can have a major effect on seizure disorders. Mol Cell Biochem 2009; 328: 49-56.
20. Dag E, Aydin S, Ozkan Y, et al. Alteration in chromogranin A, obestatin and total ghrelin levels of saliva and serum in epilepsy cases. Peptides 2010; 31: 932-937.
21. Prodam F, Bellone S, Casara G, et al. Ghrelin levels are reduced in prepubertal epileptic children under treatment with carbamazepine or valproic acid. Epilepsia 2010; 51: 312-315.
22. Cansu A, Serdaroglu A, Camurdan O, Hirfanoglu T, Cinaz P. Serum insulin, cortisol, leptin, neuropeptide y, galanin and ghrelin levels in epileptic children receiving valproate. Horm Res Paediatr 2011; 76: 65-71.
23. Aslan A, Yildirim M, Ayyildiz M, Guven A, Agar E. The role of nitric oxide in the inhibitory effect of ghrelin against penicillin-induced epileptiform activity in rat. Neuropeptides 2009; 43: 295-302.
24. Biagini G, Torsello A, Marinelli C, et al. Beneficial effects of desacyl-ghrelin, hexarelin and EP-80317 in models of status epilepticus. Eur J Pharmacol 2011; 670: 130-136.
25. Obay BD, Tasdemir E, Tumer C, Bilgin HM, Sermet A. Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats. Peptides 2007; 28: 1214-1219.
26. Verhulst PJ, De Smet B, Saels I, et al. Role of ghrelin in the relationship between hyperphagia and accelerated gastric emptying in diabetic mice. Gastroenterology 2008; 135: 1267-1276.
27. Portelli J, Aourz N, De Bundel D, et al. Intrastrain differences in seizure susceptibility, pharmacological response and basal neurochemistry of Wistar rats. Epilepsy Res 2009; 87: 234-246.
28. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972; 32: 281-294.
29. Meurs A, Clinckers R, Ebinger G, Michotte Y, Smolders I. Seizure activity and changes in hippocampal extracellular glutamate, GABA, dopamine and serotonin. Epilepsy Res 2008; 78: 50-59.
30. De Bundel D, Schallier A, Loyens E, et al. Loss of system x(c)- formula does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility. J Neurosci 2011; 31: 5792-5803.
31. Bortolotto ZA, Amici M, Anderson WW, Isaac JT, Collingridge GL. Synaptic plasticity in the hippocampal slice preparation. Curr Protoc Neurosci 2011; 6: Unit 6. 13.
32. Anderson WW, Collingridge GL. Capabilities of the WinLTP data acquisition program extending beyond basic LTP experimental functions. J Neurosci Methods 2007; 162: 346-356.
33. Carpino PA, Lefker BA, Toler SM, et al. Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin. Bioorg Med Chem 2003; 11: 581-590.
34. Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW. High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist. Mol Endocrinol 2003; 17: 2201-2210.
35. Serby MD, Zhao H, Szczepankiewicz BG, et al. 2, 4-diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists. J Med Chem 2006; 49: 2568-2578.
36. Bednarek MA, Feighner SD, Pong SS, et al. Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 2000; 43: 4370-4376.
37. Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia 2001; 42(suppl 3): 8-12.
38. Galanopoulou AS. Mutations affecting GABAergic signaling in seizures and epilepsy. Pflugers Arch 2010; 460: 505-523.
39. Cowley MA, Smith RG, Diano S, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003; 37: 649-661.
40. van Luijtelaar G, Sitnikova E. Global and focal aspects of absence epilepsy: the contribution of genetic models. Neurosci Biobehav Rev 2006; 30: 983-1003.
41. Avoli M. The epileptic hippocampus revisited: back to the future. Epilepsy Curr 2007; 7: 116-118.
42. Damian M, Marie J, Leyris JP, et al. High constitutive activity is an intrinsic feature of the ghrelin receptor protein: a study with a functional monomeric GHS-R1a receptor reconstituted in lipid discs. J Biol Chem 2012; 287: 3630-3641.
43. Pantel J, Legendre M, Cabrol S, et al. Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 2006; 116: 760-768.
44. Camina JP, Carreira MC, El Messari S, et al. Desensitization and endocytosis mechanisms of ghrelin-activated growth hormone secretagogue receptor 1a. Endocrinology 2004; 145: 930-940.
45. Delhanty PJ, van Kerkwijk A, Huisman M, et al. Unsaturated fatty acids prevent desensitization of the human growth hormone secretagogue receptor by blocking its internalization. Am J Physiol Endocrinol Metab 2010; 299: E497-E505.
46. Holliday ND, Holst B, Rodionova EA, Schwartz TW, Cox HM. Importance of constitutive activity and arrestin-independent mechanisms for intracellular trafficking of the ghrelin receptor. Mol Endocrinol 2007; 21: 3100-3112.
47. Zhu X, Han X, Blendy JA, Porter BE. Decreased CREB levels suppress epilepsy. Neurobiol Dis 2012; 45: 253-263.
48. Jin W, Sugaya A, Tsuda T, Ohguchi H, Sugaya E. Relationship between large conductance calcium-activated potassium channel and bursting activity. Brain Res 2000; 860: 21-28.
49. Pal S, Sun D, Limbrick D, Rafiq A, DeLorenzo RJ. Epileptogenesis induces long-term alterations in intracellular calcium release and sequestration mechanisms in the hippocampal neuronal culture model of epilepsy. Cell Calcium 2001; 30: 285-296.
50. 2+]I increase induced by ATP and bradykinin in PC12 cells. J Pharmacol Exp Ther 2005; 313: 720-730.
51. Imazawa M, Kabuto Y, Miyamoto K, Nishimura S, Yagi K. Inositol trisphosphate (IP3) receptors and epileptic seizure. Jpn J Psychiatry Neurol 1989; 43: 465-468.
52. Zhang B, Wong M. Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat. Epilepsia 2012; 53: 506-511.
53. Yokoyama N, Mori N, Kumashiro H. Chemical kindling induced by cAMP and transfer to electrical kindling. Brain Res 1989; 492: 158-162.
54. Williams SF, Colling SB, Whittington MA, Jefferys JG. Epileptic focus induced by intrahippocampal cholera toxin in rat: time course and properties in vivo and in vitro. Epilepsy Res 1993; 16: 137-146.
55. Chen G, Pan B, Hawver DB, Wright CB, Potter WZ, Manji HK. Attenuation of cyclic AMP production by carbamazepine. J Neurochem 1996; 67: 2079-2086.
56. Higashima M, Ohno K, Koshino Y. Cyclic AMP-mediated modulation of epileptiform afterdischarge generation in rat hippocampal slices. Brain Res 2002; 949: 157-161.
57. Rocha L, Orozco-Suarez S, Alonso-Vanegas M, et al. Temporal lobe epilepsy causes selective changes in mu opioid and nociceptin receptor binding and functional coupling to G-proteins in human temporal neocortex. Neurobiol Dis 2009; 35: 466-473.
58. Caterina MJ, Leffler A, Malmberg AB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000; 288: 306-313.
59. Szallasi A. Vanilloid (capsaicin) receptors in health and disease. Am J Clin Pathol 2002; 118: 110-121.
60. Moran MM, McAlexander MA, Biro T, Szallasi A. Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov 2011; 10: 601-620.
61. Fehrentz JA, Moulin A, Blayo L, et al. Ghrelin receptor ligands: from peptide to peptidomimetic, design and synthesis to clinical studies. Presented at the Belgian Peptide Group Meeting; February 10, 2012; Brussels.
62. Michel MC, Alewijnse AE. Ligand-directed signaling: 50 ways to find a lover. Mol Pharmacol 2007; 72: 1097-1099.
63. Portelli J, Michotte Y, Smolders I. Ghrelin - an emerging new anticonvulsant neuropeptide. Epilepsia 2012; 53: 585-595.
64. Atcha Z, Chen WS, Ong AB, et al. Cognitive enhancing effects of ghrelin receptor agonists. Psychopharmacology (Berl) 2009; 206: 415-427.
65. Carlini VP, Monzon ME, Varas MM, et al. Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun 2002; 299: 739-743.
66. Beck H, Goussakov IV, Lie A, Helmstaedter C, Elger CE. Synaptic plasticity in the human dentate gyrus. J Neurosci 2000; 20: 7080-7086.