Login Register Cart 0
Generic placeholder image

Current Neuropharmacology

Editor-in-Chief

ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Perspective

The Orexin System: A Potential Player in the Pathophysiology of Absence Epilepsy

Author(s): Roberta Celli* and Gilles Van Luijtelaar*

Volume 20, Issue 7, 2022

Published on: 30 March, 2022

Page: [1254 - 1260] Pages: 7

DOI: 10.2174/1570159X19666211215122833

Abstract

Background: Absence epilepsy is characterized by the presence of spike-and-wave discharges (SWDs) at the EEG generated within the cortico-thalamo-cortical circuit. The molecular mechanisms involved in the pathophysiology of absence epilepsy are only partially known. WAG/Rij rats older than 2-3 months develop spontaneous SWDs, and they are sensitive to anti- absence medications. Hence, WAG/Rij rats are extensively used as a model for absence epilepsy with predictive validity.

Objective: The aim of the study was to examine the possibility that the orexin system, which supports the wake status in experimental animals and humans, plays a role in the pathophysiology of absence seizures.

Methods: The perspective grounds its method from recent literature along with measurements of orexin receptor type-1 (OX1) protein levels in the thalamus and somatosensory cortex of WAG/Rij rats and non-epileptic Wistar control rats at two ages (25 days and 6-7 months). OX1 protein levels were measured by immunoblotting.

Results: The analysis of the current literature suggests that the orexin system might be involved in the pathophysiology of absence epilepsy and might be targeted by therapeutic intervention. Experimental data are in line with this hypothesis, showing that OX1 protein levels were reduced in the thalamus and somatosensory cortex of symptomatic WAG/Rij rats (6-7 months of age) with respect to non-epileptic controls, whereas these differences were not seen in pre-symptomatic, 25 days-old WAG/Rij rats.

Conclusion: This perspective might pave the way for future studies on the involvement of the orexinergic system in the pathophysiology of SWDs associated with absence epilepsy and its comorbidities.

Keywords: Absence epilepsy, SWDs, cortico-thalamo-cortical network, sleep disturbance, orexin system, OX1.

« Previous Next »
[1]
Coenen AM, Van Luijtelaar EL. Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behav Genet 2003; 33(6): 635-55.
[http://dx.doi.org/10.1023/A:1026179013847] [PMID: 14574120]
[2]
Steriade M. Neuronal substrates of sleep and epilepsy. Cambridge University Press 2003.
[3]
Meeren HK, Pijn JP, Van Luijtelaar EL, Coenen AM, Lopes da Silva FH. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. J Neurosci 2002; 22(4): 1480-95.
[http://dx.doi.org/10.1523/JNEUROSCI.22-04-01480.2002] [PMID: 11850474]
[4]
Blumenfeld H. Cellular and network mechanisms of spike-wave seizures. Epilepsia 2005; 46(Suppl. 9): 21-33.
[http://dx.doi.org/10.1111/j.1528-1167.2005.00311.x] [PMID: 16302873]
[5]
Dinner DS, Luders HO. Epilepsy and Sleep: Physiological and Clinical Relationships. San Diego: Academic Press 2001.
[6]
Maganti R, Sheth RD, Hermann BP, Weber S, Gidal BE, Fine J. Sleep architecture in children with idiopathic generalized epilepsy. Epilepsia 2005; 46(1): 104-9.
[http://dx.doi.org/10.1111/j.0013-9580.2005.06804.x] [PMID: 15660775]
[7]
Smyk MK, van Luijtelaar G. Circadian rhythms and epilepsy: A suitable case for absence epilepsy. Front Neurol 2020; 11: 245.
[http://dx.doi.org/10.3389/fneur.2020.00245] [PMID: 32411068]
[8]
Gandolfo G, Romettino S, Gottesmann C, Van Luijtelaar G, Coenen A. Genetically epileptic rats show a pronounced intermediate stage of sleep. Physiol Behav 1990; 47(1): 213-5.
[http://dx.doi.org/10.1016/0031-9384(90)90063-A] [PMID: 2326339]
[9]
van Luijtelaar G, Bikbaev A. Midfrequency cortico-thalamic oscillations and the sleep cycle: genetic, time of day and age effects. Epilepsy Res 2007; 73(3): 259-65.
[http://dx.doi.org/10.1016/j.eplepsyres.2006.11.002] [PMID: 17156975]
[10]
van Luijtelaar G, Wilde M, Citraro R, Scicchitano F, van Rijn C. Does antiepileptogenesis affect sleep in genetic epileptic rats? Int J Psychophysiol 2012; 85(1): 49-54.
[http://dx.doi.org/10.1016/j.ijpsycho.2011.09.010] [PMID: 21946343]
[11]
Kostopoulos GK. Spike-and-wave discharges of absence seizures as a transformation of sleep spindles: the continuing development of a hypothesis. Clin Neurophysiol 2000; 111(Suppl. 2): S27-38.
[http://dx.doi.org/10.1016/S1388-2457(00)00399-0] [PMID: 10996552]
[12]
Szabo ST, Thorpy MJ, Mayer G, Peever JH, Kilduff TS. Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy. Sleep Med Rev 2019; 43: 23-36.
[http://dx.doi.org/10.1016/j.smrv.2018.09.006] [PMID: 30503715]
[13]
Bassetti CLA, Adamantidis A, Burdakov D, et al. Narcolepsy - clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol 2019; 15(9): 519-39.
[http://dx.doi.org/10.1038/s41582-019-0226-9] [PMID: 31324898]
[14]
Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron 2017; 93(4): 747-65.
[http://dx.doi.org/10.1016/j.neuron.2017.01.014] [PMID: 28231463]
[15]
de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998; 95(1): 322-7.
[http://dx.doi.org/10.1073/pnas.95.1.322] [PMID: 9419374]
[16]
Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92(4): 573-85.
[http://dx.doi.org/10.1016/S0092-8674(00)80949-6] [PMID: 9491897]
[17]
Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998; 18(23): 9996-10015.
[http://dx.doi.org/10.1523/JNEUROSCI.18-23-09996.1998] [PMID: 9822755]
[18]
van den Pol AN. Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci 1999; 19(8): 3171-82.
[http://dx.doi.org/10.1523/JNEUROSCI.19-08-03171.1999] [PMID: 10191330]
[19]
Lu XY, Bagnol D, Burke S, Akil H, Watson SJ. Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm Behav 2000; 37(4): 335-44.
[http://dx.doi.org/10.1006/hbeh.2000.1584] [PMID: 10860677]
[20]
Marcus JN, Aschkenasi CJ, Lee CE, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001; 435(1): 6-25.
[http://dx.doi.org/10.1002/cne.1190] [PMID: 11370008]
[21]
Ammoun S, Holmqvist T, Shariatmadari R, et al. Distinct recognition of OX1 and OX2 receptors by orexin peptides. J Pharmacol Exp Ther 2003; 305(2): 507-14.
[http://dx.doi.org/10.1124/jpet.102.048025] [PMID: 12606634]
[22]
Wang C, Wang Q, Ji B, et al. The orexin/receptor system: Molecular mechanism and therapeutic potential for neurological diseases. Front Mol Neurosci 2018; 11: 220.
[http://dx.doi.org/10.3389/fnmol.2018.00220] [PMID: 30002617]
[23]
Peltonen HM, Magga JM, Bart G, et al. Involvement of TRPC3 channels in calcium oscillations mediated by OX(1) orexin receptors. Biochem Biophys Res Commun 2009; 385(3): 408-12.
[http://dx.doi.org/10.1016/j.bbrc.2009.05.077] [PMID: 19464259]
[24]
Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 1998; 438(1-2): 71-5.
[http://dx.doi.org/10.1016/S0014-5793(98)01266-6] [PMID: 9821961]
[25]
Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 2001; 103(3): 777-97.
[http://dx.doi.org/10.1016/S0306-4522(01)00033-1] [PMID: 11274794]
[26]
Steriade M, Glenn LL. Neocortical and caudate projections of intralaminar thalamic neurons and their synaptic excitation from midbrain reticular core. J Neurophysiol 1982; 48(2): 352-71.
[http://dx.doi.org/10.1152/jn.1982.48.2.352] [PMID: 6288887]
[27]
Jones EG. The Thalamus. New York: Plenum Press 1985.
[http://dx.doi.org/10.1007/978-1-4615-1749-8]
[28]
Bayer L, Serafin M, Eggermann E, et al. Exclusive postsynaptic action of hypocretin-orexin on sublayer 6b cortical neurons. J Neurosci 2004; 24(30): 6760-4.
[http://dx.doi.org/10.1523/JNEUROSCI.1783-04.2004] [PMID: 15282280]
[29]
Govindaiah G, Cox CL. Modulation of thalamic neuron excitability by orexins. Neuropharmacology 2006; 51(3): 414-25.
[http://dx.doi.org/10.1016/j.neuropharm.2006.03.030] [PMID: 16713607]
[30]
Fejerman N. Nonepileptic disorders imitating generalized idiopathic epilepsies. Epilepsia 2005; 46(Suppl. 9): 80-3.
[http://dx.doi.org/10.1111/j.1528-1167.2005.00317.x] [PMID: 16302879]
[31]
Plazzi G, Tinuper P. Praxis-induced seizures misdiagnosed as cataplexy: a case report. Mov Disord 2008; 23(14): 2105-7.
[http://dx.doi.org/10.1002/mds.22252] [PMID: 18709676]
[32]
Lagrange AH, Blaivas M, Gomez-Hassan D, Malow BA. Rasmussen’s syndrome and new-onset narcolepsy, cataplexy, and epilepsy in an adult. Epilepsy Behav 2003; 4(6): 788-92.
[http://dx.doi.org/10.1016/j.yebeh.2003.08.030] [PMID: 14698722]
[33]
Yang Z, Liu X, Dong X, Qin J, Li J, Han F. Epilepsy and narcolepsy-cataplexy in a child. J Child Neurol 2012; 27(6): 807-10.
[http://dx.doi.org/10.1177/0883073811432888] [PMID: 22596015]
[34]
van Luijtelaar G, Sitnikova E. Global and focal aspects of absence epilepsy: the contribution of genetic models. Neurosci Biobehav Rev 2006; 30(7): 983-1003.
[http://dx.doi.org/10.1016/j.neubiorev.2006.03.002] [PMID: 16725200]
[35]
Celli R, Wall MJ, Santolini I, et al. Pharmacological activation of mGlu5 receptors with the positive allosteric modulator VU0360172, modulates thalamic GABAergic transmission. Neuropharmacology 2020; 178: 108240.
[http://dx.doi.org/10.1016/j.neuropharm.2020.108240] [PMID: 32768418]
[36]
Santolini I, Celli R, Cannella M, et al. EuroEPINOMICS CoGIE Consortium; Genetic Commission of Italian League Against Epilepsy (LICE), Moyanova, S.; Ngomba, R.T.; van Luijtelaar, G.; Battaglia, G.; Bruno, V.; Striano, P.; Nicoletti, F. Alterations in the α2 δ ligand, thrombospondin-1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies. Epilepsia 2017; 58(11): 1993-2001.
[http://dx.doi.org/10.1111/epi.13898] [PMID: 28913875]
[37]
Chrobok L, Palus-Chramiec K, Chrzanowska A, Kepczynski M, Lewandowski MH. Multiple excitatory actions of orexins upon thalamo-cortical neurons in dorsal lateral geniculate nucleus - implications for vision modulation by arousal. Sci Rep 2017; 7(1): 7713.
[http://dx.doi.org/10.1038/s41598-017-08202-8] [PMID: 28794459]
[38]
Ishibashi M, Takano S, Yanagida H, et al. Effects of orexins/hypocretins on neuronal activity in the paraventricular nucleus of the thalamus in rats in vitro. Peptides 2005; 26(3): 471-81.
[http://dx.doi.org/10.1016/j.peptides.2004.10.014] [PMID: 15652654]
[39]
Li Y, Li S, Wei C, Wang H, Sui N, Kirouac GJ. Orexins in the paraventricular nucleus of the thalamus mediate anxiety- like responses in rats. Psychopharmacology (Berl) 2010; 212(2): 251-65.
[http://dx.doi.org/10.1007/s00213-010-1948-y] [PMID: 20645079]
[40]
Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 2011; 3(8): a003947.
[http://dx.doi.org/10.1101/cshperspect.a003947] [PMID: 21746798]
[41]
Takenoshita S, Sakai N, Chiba Y, Matsumura M, Yamaguchi M, Nishino S. An overview of hypocretin based therapy in narcolepsy. Expert Opin Investig Drugs 2018; 27(4): 389-406.
[http://dx.doi.org/10.1080/13543784.2018.1459561] [PMID: 29623725]
[42]
Irukayama-Tomobe Y, Yanagisawa M. Development of a therapeutic drug for narcolepsy. Brain Nerve 2018; 70(11): 1255-63.
[PMID: 30416119]
[43]
Futamura A, Suzuki R, Tamura Y, et al. Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia. Bioorg Med Chem 2020; 28(13): 115489.
[http://dx.doi.org/10.1016/j.bmc.2020.115489] [PMID: 32482533]
[44]
Roch C, Bergamini G, Steiner MA, Clozel M. Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia. Psychopharmacology (Berl) 2021; 238(10): 2693-708.
[http://dx.doi.org/10.1007/s00213-021-05954-0] [PMID: 34415378]
[45]
Koebisu M, Koyama N, Nishida M, Muramoto K. Preclinical and clinical efficacy of orexin receptor antagonist Lemborexant (Dayvigo®) on insomnia patients. Nippon Yakurigaku Zasshi 2021; 156(2): 114-9.
[http://dx.doi.org/10.1254/fpj.20093] [PMID: 33642529]
[46]
Haynes AC, Jackson B, Chapman H, et al. A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 2000; 96(1-2): 45-51.
[http://dx.doi.org/10.1016/S0167-0115(00)00199-3] [PMID: 11102651]
[47]
Ishii Y, Blundell JE, Halford JC, et al. Satiety enhancement by selective orexin-1 receptor antagonist SB-334867: influence of test context and profile comparison with CCK-8S. Behav Brain Res 2005; 160(1): 11-24.
[http://dx.doi.org/10.1016/j.bbr.2004.11.011] [PMID: 15836896]
[48]
Parise EM, Lilly N, Kay K, et al. Evidence for the role of hindbrain orexin-1 receptors in the control of meal size. Am J Physiol Regul Integr Comp Physiol 2011; 301(6): R1692-9.
[http://dx.doi.org/10.1152/ajpregu.00044.2011] [PMID: 21957165]
[49]
Mehr JB, Mitchison D, Bowrey HE, James MH. Sleep dysregulation in binge eating disorder and “food addiction”: the orexin (hypocretin) system as a potential neurobiological link. Neuropsychopharmacology 2021; 46(12): 2051-61.
[http://dx.doi.org/10.1038/s41386-021-01052-z] [PMID: 34145404]
[50]
De Caro C, Di Cesare Mannelli L, Branca JJV, et al. Pain modulation in WAG/Rij epileptic rats (a genetic model of absence epilepsy): Effects of biological and pharmacological histone deacetylase inhibitors. Front Pharmacol 2020; 11: 549191.
[http://dx.doi.org/10.3389/fphar.2020.549191] [PMID: 33343343]
[51]
Sarkisova K, van Luijtelaar G. The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression [corrected]. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35(4): 854-76.
[http://dx.doi.org/10.1016/j.pnpbp.2010.11.010] [PMID: 21093520]
[52]
Shariq AS, Rosenblat JD, Alageel A, et al. Evaluating the role of orexins in the pathophysiology and treatment of depression: A comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry 2019; 92: 1-7.
[http://dx.doi.org/10.1016/j.pnpbp.2018.12.008] [PMID: 30576764]
[53]
Razavi BM, Hosseinzadeh H. A review of the role of orexin system in pain modulation. 2017; 90: 187-93.
[http://dx.doi.org/10.1016/j.biopha.2017.03.053]
[54]
Moyanova S, De Fusco A, Santolini I, et al. Abnormal Hippocampal Melatoninergic System: A Potential Link between Absence Epilepsy and Depression-Like Behavior in WAG/Rij Rats? Int J Mol Sci 2018; 19(7): 1973.
[http://dx.doi.org/10.3390/ijms19071973] [PMID: 29986414]

Rights & Permissions Print Cite
Article Metrics
46
1
World Autism Awareness Day
© 2024 Bentham Science Publishers | Privacy Policy