Abstract
Neuroanatomical localization and physiological properties of galanin suggest that the peptide may be involved in the regulation of seizures. Indeed, administration of galanin receptor agonists into brain areas pertinent to the initiation and propagation of epileptic activity attenuated seizure responses under conditions of animal models of epilepsy; pharmacological blocking of galanin receptors exerted proconvulsant effects. Functional deletion of both galanin and galanin type 1 receptor genes produced transgenic mice with either spontaneous seizure phenotype, or with enhanced susceptibility to seizure stimuli. At the same time, overexpression of galanin in seizure pathways, using both transgenic and virus vector transfection techniques, hindered the epileptic process. Galanin exerts anticonvulsant effects through both type 1 and type 2 receptors, with distinct downstream signaling cascades. Several synthetic agonists of galanin receptors with optimized bioavailability have been synthesized and inhibited experimental seizures upon systemic administration, thus opening an opportunity for the development of galanin-based antiepileptic drugs.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Tatemoto K, Rökaeus A, Jörnvall H, McDonald TJ, Mutt V (1983) Galanin – a novel biologically active peptide from porcine intestine. FEBS Lett 28:124–128
Mazarati AM, Halaszi E, Telegdy G (1992) Anticonvulsive effects of galanin administered into the central nervous system upon the picrotoxin-kindled seizure syndrome in rats. Brain Res 589:164–166
Zini S, Roisin M, Langel U, Bartfai T, Ben-Ari Y (1993) Galanin reduces release of endogenous excitatory amino acids in the rat hippocampus. Eur J Pharmacol 245:1–7
Heinemann U, Beck H, Dreier JP, Ficker E, Stabel J, Zhang CL (1992) The dentate gyrus as a regulated gate for the propagation of epileptiform activity. Epilepsy Res Suppl 7:273–280
Hökfelt T, Xu ZQ, Shi TJ, Holmberg K, Zhang X (1998) Galanin in ascending systems: focus on coexistence with 5-hydroxytryptamine and noradrenaline. Ann NY Acad Sci 863:252–263
Xu ZQ, Shi TJ, Hökfelt T (1998) Galanin/GMAP- and NPY-like immunoreactivities in locus coeruleus and noradrenergic nerve terminals in the hippocampal formation and cortex with notes on the galanin-R1 and -R2 receptors. J Comp Neurol 392:227–251
Consolo S, Baldi G, Russi G, Civenni G, Bartfai T, Vezzani A (1994) Impulse flow dependency of galanin release in vivo in the rat ventral hippocampus. Proc Natl Acad Sci USA 91:8047–8051
Lamour Y, Senut MC, Dutar P, Bassant MH (1988) Neuropeptides and septo-hippocampal neurons: electrophysiological effects and distributions of immunoreactivity. Peptides 9:1351–1359
Melander T, Staines WA, Rökaeus A (1986) Galanin-like immunoreactivity in cholinergic neurons of the septum-basal forebrain complex projecting to the hippocampus of the rat. Neuroscience 19:223–240
Mazarati AM (2004) Galanin and galanin receptors in epilepsy. Neuropeptides 38:331–343
Heinemann U, Schmitz D, Eder C, Gloveli T (2000) Properties of entorhinal cortex projection cells to the hippocampal formation. Ann NY Acad Sci 911:112–126
Mazarati AM, Hohmann JG, Bacon A, Liu H, Sankar R, Steiner RA, Wynick D, Wasterlain CG (2000) Modulation of hippocampal excitability and seizures by galanin. J Neurosci 20:6276–6281
Pereira de Vasconcelos A, Mazarati AM, Wasterlain CG, Nehlig A (1999) Self-sustaining status epilepticus after a brief electrical stimulation of the perforant path: a 2-deoxyglucose study. Brain Res 838:110–118
Wasterlain CG, Liu H, Mazarati AM, Baldwin RA, Shirasaka Y, Katsumori H, Thompson KW, Sankar R, Pereira de Vasconselos A, Nehlig A (2000) Self-sustaining status epilepticus: a condition maintained by potentiation of glutamate receptors and by plastic changes in substance P and other peptide neuromodulators. Epilepsia 41(Suppl 6):S134–S143
Mazarati AM, Liu H, Soomets U, Sankar R, Shin D, Katsumori H, Langel U, Wasterlain CG (1998) Galanin modulation of seizures and seizure modulation of hippocampal galanin in animal models of status epilepticus. J Neurosci 18:10070–10077
Mazarati A, Wasterlain CG (2002) Anticonvulsant effects of four neuropeptides in the rat hippocampus during self-sustaining status epilepticus. Neurosci Lett 331:123–127
Schlifke I, Kuteeva E, Hökfelt T, Kokaia M (2006) Galanin expressed in the excitatory fibers attenuates synaptic strength and generalized seizures in the piriform cortex of mice. Exp Neurol 200:398–406
Kokaia M, Holmberg K, Nanobashvili A, Xu ZD, Kokaia Z, Lendahl U, Hilke S, Theodorsson E, Kahli U, Bartfaii T, Lindvall O, Hökfelt T (2001) Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin. Proc Natl Acad Sci USA 98:14006–14011
Haberman RP, Samulski RJ, McCown TJ (2003) Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion. Nat Med 9:1076–1080
McCown TJ (2006) Adeno-associated virus-mediated expression and constitutive secretion of galanin suppresses limbic seizure activity in vivo. Mol Ther 14:63–68
Lin EJ, Richichi C, Young D, Baer K, Vezzani A, During MJ (2003) Recombinant AAV-mediated expression of galanin in rat hippocampus suppresses seizure development. Eur J Neurosci 18:2087–2092
Kanter-Schlifke I, Toft Sorensen A, Ledri M, Kuteeva E, Hökfelt T, Kokaia M (2007) Galanin gene transfer curtails generalized seizures in kindled rats without altering hippocampal synaptic plasticity. Neuroscience 150:984–992
Hökfelt T, Millhorn D, Seroogy K, Tsuruo Y, Ceccatelli S, Lindh B, Meister B, Melander T, Schalling M, Bartfai T (1987) Coexistence of peptides with classical neurotransmitters. Experientia 43:768–780
Arabadzisz D, Antal K, Parpan F, Emri Z, Fritschy JM (2005) Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus. Exp Neurol 194:76–90
Koh S (2005) Microarray analysis of postictal gene expression: transcriptional regulation of neuropeptides. Neuropeptides 39:56–57
Branchek TA, Smith KE, Gerald C, Walker MW (2000) Galanin receptor subtypes. Trends Pharmacol Sci 21:109–117
Burazin TCD, Larm JA, Ryan MC, Gundlach AL (2000) Galanin-R1 and -R2 receptor mRNA expression during the development of rat brain suggests differential subtype involvement in synaptic transmission and plasticity. Eur J Neurosci 12:2901–2917
O’Donnel D, Sultan A, Wahlestedt C, Walker P (1999) Expression of the novel galanin receptor subtype GALR2 in the adult rat CNS: distinct distribution from GALR1. J Comp Neurol 409:469–481
Depczynski B, Nichol K, Fathi Z, Iismaa T, Shine J, Cunningham A (1998) Distribution and characterization of the cell types expressing GALR2 mRNA in brain and pituitary gland. Ann NY Acad Sci 863:120–128
Gustafson EL, Smith KE, Durkin MM, Gerald C, Branchek TA (1996) Distribution of a rat galanin receptor mRNA in rat brain. Neuroreport 7:953–957
Zini S, Roisin MP, Armengaud C, Ben-Ari Y (1993) Effects of potassium channels moduators on the release of glutamate induced by ischaemic-like conditions in rat hippocampal slices. Neurosci Lett 153:202–205
Floren A, Land T, Langel U (2000) Galanin receptor subtypes and ligand binding. Neuropeptides 34:331–337
Mazarati AM, Lu X, Kilk K, Langel U, Wasterlain CG, Bartfai T (2004) Galanin type 2 receptors regulate neuronal survival, susceptibility to seizures and seizure-induced neurogenesis in the dentate gyrus. Eur J Neurosci 19:3235–3244
Hua XY, Hayes CS, Hofer A, Fitzsimmons B, Kilk K, Langel U, Bartfai T, Yaksh TL (2004) Galanin acts at GalR1 receptors in spinal antinociception: synergy with morphine and AP-5. J Pharmacol Exp Ther 308:574–582
Kerekes N, Mennicken F, O’Donnell D, Hökfelt T, Hill RH (2003) Galanin increases membrane excitability and enhances Ca2+ currents in adult, acutely dissociated dorsal root ganglion neurons. Eur J Neurosci 11:2957–2966
Liu HX, Brumovsky P, Schmidt R, Brown W, Payza K, Hodzic L, Pou C, Godbout C, Hökfelt T (2001) Receptor subtype-specific pronociceptive and analgesic actions of galanin in the spinal cord: selective actions via GalR1 and GalR2 receptors. Proc Natl Acad Sci USA 98:9960–9964
Saar K, Mazarati AM, Mahlapuu R, Hallnemo G, Soomets U, Kilk K, Hellberg S, Pooga M, Tolf BR, Shi TS et al (2002) Anticonvulsant activity of a nonpeptide galanin receptor agonist. Proc Natl Acad Sci USA 99:7136–7141
Jacoby AS, Hort YJ, Constantinescu G, Shine J, Iismaa TP (2002) Critical role for GALR1 galanin receptor in galanin regulation of neuroendocrine function and seizure activity. Mol Brain Res 107:195–200
Jacoby AS, Holmes F, Hort YJ, Shine J, Iismaa T (2002) Phenotypic analysis of Galr1 knockout mice reveals a role for GALR1 galanin receptor in modulating seizure activity but not nerve regeneration. Lett Pept Sci 8:139–146
Fetissov SO, Jacoby AS, Brumovsky PR, Shine J, Iismaa TP, Hökfelt T (2003) Altered hippocampal expression of neuropeptides in deizure-prone GALR1 knockout mice. Epilepsia 44:1022–1033
McColl CD, Jacoby AS, Shine J, Iismaa TP, Bekkers JM (2006) Galanin receptor-1 knockout mice exhibit spontaneous epilepsy, abnormal EEGs and altered inhibition in the hippocampus. Neuropharmacology 50:209–218
Mazarati A, Lu X, Shinmei S, Badie-Mahdavi H, Bartfai T (2004) Patterns of seizures, hippocampal injury and neurogenesis in three models of status epilepticus in galanin receptor type 1 (galr1) knockout mice. Neuroscience 128:431–441
Pooga M, Soomets U, Hällbrink M, Valkna A, Saar K, Rezaei K, Kahl U, Hao J-X, Xu X-J, Wiesenfeld-Hallin Z et al (1998) Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Nat Biotechnol 16:857–861
Gottsch ML, Zeng H, Hohmann JG, Weinshenker D, Clifton DK, Steiner RA (2005) Phenotypic analysis of mice deficient in the type 2 galanin receptor (GALR2). Mol Cell Biol 25:4804–4811
Lu X, Mazarati A, Sanna P, Shinmei S, Bartfai T (2005) Distribution and differential regulation of galanin receptor subtypes in rat brain: effects of seizure activity. Neuropeptides 39:147–152
Palazzi E, Felinska S, Zambelli M, Fisone G, Bartfai T, Consolo S (1991) Galanin reduces carbachol stimulation of phosphoinositide turnover in rat ventral hippocampus by lowering Ca2+ influx through voltage-sensitive Ca2+ channels. J Neurochem 56:739–747
Mazarati AM, Sollenberg U, Lundström L, Shin D, Langel U, Sankar R (2006) Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: the effects of subtype selective agonists and the role of G-protein mediated signaling. J Pharmacol Exp Ther 318:700–708
Lundström L, Sollenberg U, Brewer A, Kouya PF, Zheng K, Xu X-J, Sheng X, Robinson JK, Wiesenfeld-Hallin Z, Xu Z-Q et al (2005) A galanin receptor subtype 1 specific agonist. Int J Pept Res Ther 11:17–27
Azmitia EC, Segal M (1978) An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. Br J Pharmacol 121:1180–1186
Jacobs BL, Wise WD, Taylor KM (1974) Differential behavioral and neurochemical effects following lesions to the dorsal or median raphe nuclei in rats. Brain Res 79:353–361
Mazarati AM, Baldwin RA, Shinmei S, Sankar R (2005) In vivo interaction between serotonin and galanin receptors types 1 and 2 in the dorsal raphe: implication for limbic seizures. J Neurochem 95:1495–1503
Bartfai T, Lu T, Badie-Mahdavi HM, Barr AM, Mazarati A, Hua X, Yaksh T, Haberhauer G, Trembleau L, Conde Ceide S et al (2004) Galmic, a non peptide galanin receptor agonist, affects behaviors in seizure, pain and forced swim tests. Proc Natl Acad Sci USA 101:10470–10475
Adkins EM, Smith MD, Pruess T, Grussendorf E, Green G, Bulaj G, White HS (2007) NAX-5055: A metabolically stable galanin-based neuropeptide with potent anticonvulsant and antinociceptive actions. American Epilepsy Society, Philadelphia, PA, p 3.121
Flynn SP, Green B, Bulaj G, White HS (2007) Effects of NAX-5055 on kindling acquisition in the mouse corneal kindling model. American Epilepsy Society, Philadelphia, PA, p 3.104
Acknowledgments
Supported by research grant NS43409 from the National Institutes of Health.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Basel AG
About this chapter
Cite this chapter
Lerner, J.T., Sankar, R., Mazarati, A.M. (2010). Galanin and Epilepsy. In: Hökfelt, T. (eds) Galanin. Experientia Supplementum, vol 102. Springer, Basel. https://doi.org/10.1007/978-3-0346-0228-0_13
Download citation
DOI: https://doi.org/10.1007/978-3-0346-0228-0_13
Published:
Publisher Name: Springer, Basel
Print ISBN: 978-3-0346-0227-3
Online ISBN: 978-3-0346-0228-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)