Genetik absans epilepsili WAG/Rij sıçanlarda kardiyovasküler değişiklikler: Kronik etosüksimid tedavisinin etkileri

Year 2020, Volume: 45 Issue: 3, 769 - 777, 30.09.2020

Tuğçe Demirtaş Şahin , Tijen Utkan , Ayşe Karson Yusufhan Yazır , Erdal Karaoz

https://doi.org/10.17826/cumj.724491

Abstract

Amaç: Bu çalışmada, genetik absans epilepsili WAG/Rij sıçanlarda kronik etosüksimid (ETS) tedavisinin absans nöbetler ve gözlenebilecek olası kardiyovasküler değişiklikler üzerindeki etkilerinin araştırılması amaçlanmıştır.
Gereç ve Yöntem: İki aylık erkek Wistar ve WAG/Rij sıçanlar; Wistar kontrol, Wistar ETS, WAG/Rij kontrol ve WAG/Rij ETS gruplarına ayrılmıştır (n=20). ETS grupları 3 ay boyunca kronik ETS tedavisi (oral, 300 mg/kg/gün) almışlardır. Üç aylık tedavi periyodunun sonunda EEG kayıtları kullanılarak diken dalga deşarjlarının (DDD) toplam süre, ortalama süre ve sayısı değerlendirilmiştir. Ortalama arteriyel kan basıncı (OAB) ve kalp hızı (KH) ölçümleri gerçekleştirilmiştir.
Bulgular: ETS tedavisi WAG/Rij sıçanlarda DDD’leri toplam süre, ortalama süre ve sayı açısından anlamlı olarak azaltmıştır. OAB, WAG/Rij kontrol grubunda Wistar kontrol grubuna göre anlamlı olarak artmıştır. KH, Wistar ETS grubunda Wistar kontrol grubuna göre anlamlı olarak azalmıştır. KCl aracılı kasılma yanıtlarında Wistar kontrol grubuna göre Wistar ETS grubunda anlamlı artma, WAG/Rij kontrol grubunda anlamlı azalma saptanmıştır.
Sonuç: Sonuçlarımız OAB ve vasküler reaktivitenin WAG/Rij sıçanlarda arttığını göstermiştir. ETS tedavisi, WAG/Rij sıçanlarda kardiyovasküler parametreleri değiştirmezken Wistar sıçanlarda KH ve vasküler reaktiviteyi azaltmış OAB’yi etkilememiştir. Bu değişikliklerde T-tipi Ca++ kanallarının rol oynayabileceği düşünülmektedir.

Keywords

Absans epilepsi, WAG/Rij, etosüksimid, kalp hızı, kan basıncı, vasküler reaktivite

Supporting Institution

TÜBİTAK

Project Number

SBAG / 114S481

Cardiovascular changes in genetic absence epileptic WAG/Rij rats: Effects of chronic ethosuximide treatment

Abstract

Purpose: The aim of this study was to investigate the effects of chronic ethosuximide (ETX) treatment on absence seizures and cardiovascular parameters in WAG/Rij rats with genetic absence epilepsy.
Materials and Methods: Eight-weeks old, male Wistar and WAG/Rij rats were divided into four groups (n=20): Wistar control, Wistar ETX, WAG/Rij control and WAG/Rij ETX. ETX groups received chronic ETX treatment (oral, 300 mg/kg/day) for 3 months. At the end of the 3-month-treatment period; the total and mean duration, also number of spike wave discharges (SWDs) were evaluated using EEG recordings. Mean arterial blood pressure (MAP) and heart rate (HR) measurements were performed.
Results: ETX treatment significantly decreased the duration and frequency of SWDs in WAG/Rij rats. MAP in WAG/Rij control group was markedly higher than Wistar control group. In Wistar ETX group, HR was significantly slower than Wistar control group. KCl-induced contraction response enhanced in Wistar ETX group and diminished in WAG/Rij control group compared to Wistar control group.
Conclusion: Increased MAP and vascular reactivity in WAG/Rij rats. ETX treatment did not alter cardiovascular parameters in WAG/Rij rats whereas the treatment decreased the HR and vascular reactivity without affecting MAP in Wistar rats. T-type Ca++ channels may play a role in these changes. 

Keywords

Absence epilepsy, WAG/Rij, ethosuximide, heart rate, blood pressure, vascular reactivity

Project Number

SBAG / 114S481

References

• Jansen K, Lagae L. Cardiac changes in epilepsy. Seizure. 2010;19(8):455-60.
• Velagapudi P, Turagam M, Laurence T, Kocheril A. Cardiac arrhythmias and sudden unexpected death in epilepsy (SUDEP). Pacing Clin Electrophysiol. 2012;35(3):363-70.
• Depaulis A, Charpier S. Pathophysiology of absence epilepsy: Insights from genetic models. Neurosci Lett. 2018;667:53-65.
• Depaulis A, van Luijtelaar G. Genetic models of absence epilepsy in the rat. In Models of Seizures and Epilepsy (Eds A Pitkänen, PA Schwartkroin, SL Moshe):233-248. Amsterdam, Elsevier, 2006.
• Karson AB, Aker R, Ateş N, Onat F. Cardiovascular effects of intracerebroventricular bicuculline in rats with absence seizures. Epilepsy Res. 1999;34(2-3):231-9.
• Aker RG, Onat FY. Cardiovascular regulation through hypothalamic GABA(A) receptors in a genetic absence epilepsy model in rat. Epilepsia. 2002;43(2):107-14.
• Yananli HR, Terzioğlu B, Goren MZ, Aker RG, Aypak C, Onat FY. Extracellular hypothalamic gamma-aminobutyric acid (GABA) and L-glutamic acid concentrations in response to bicuculline in a genetic absence epilepsy rat model. J Pharmacol Sci. 2008;106(2):301-9.
• Powell KL, Jones NC, Kennard JT, Ng C, Urmaliya V, Lau S et al. HCN channelopathy and cardiac electrophysiologic dysfunction in genetic and acquired rat epilepsy models. Epilepsia. 2014;55(4):609-20.
• Cheong E, Shin HS. T-type Ca++ channels in absence epilepsy. Biochim Biophys Acta. 2013;1828(7):1560-71.
• Kessler SK, McGinnis E. A Practical Guide to Treatment of Childhood Absence Epilepsy. Paediatr Drugs. 2019;21(1):15-24.
• Russo E, Citraro R, Scicchitano F, De Fazio S, Di Paola ED, Constanti A et al. Comparison of the antiepileptogenic effects of an early long-term treatment with ethosuximide or levetiracetam in a genetic animal model of absence epilepsy. Epilepsia. 2010;51(8):1560-9.
• Crunelli V, Leresche N. Childhood absence epilepsy: genes, channels, neurons and networks. Nat Rev Neurosci. 2002;3(5):371-82.
• Perez-Reyes E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev. 2003;83(1):117-61.
• Kim D, Song I, Keum S, Lee T, Jeong MJ, Kim SS et al. Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2+) channels. Neuron. 2001;31(1):35-45.
• Ernst WL, Zhang Y, Yoo JW, Ernst SJ, Noebels JL. Genetic enhancement of thalamocortical network activity by elevating alpha 1g-mediated low-voltage-activated calcium current induces pure absence epilepsy. J Neurosci. 2009;29(6):1615-25.
• Blumenfeld H, Klein JP, Schridde U, Vestal M, Rice T, Khera DS et al. Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia. 2008;49(3):400-9.
• Sarkisova KY, Kuznetsova GD, Kulikov MA, van Luijtelaar G. Spike-wave discharges are necessary for the expression of behavioral depression-like symptoms. Epilepsia. 2010;51(1):146-60.
• Fedosova EA, Sarkisova KIu, Kudrin VS, Narkevich VB, Klodt PM, Bazian AS. Concentrations of monoamines in the brain structures and features of behavior in the two-month old WAG/Rij rats. Zh Vyssh Nerv Deiat Im I P Pavlova. 2014;64(5):562-77.
• Svenningsen P, Andersen K, Thuesen AD, Shin HS, Vanhoutte PM, Skøtt O et al. T-type Ca(2+) channels facilitate NO-formation, vasodilatation and NO-mediated modulation of blood pressure. Pflugers Arch. 2014;466(12):2205-14.
• Harraz OF, Brett SE, Zechariah A, Romero M, Puglisi JL, Wilson SM et al. Genetic ablation of CaV3.2 channels enhances the arterial myogenic response by modulating the RyR-BKCa axis. Arterioscler Thromb Vasc Biol. 2015;35(8):1843-51.
• Mangoni ME, Traboulsie A, Leoni AL, Couette B, Marger L, Le Quang K et al. Bradycardia and slowing of the atrioventricular conduction in mice lacking CaV3.1/alpha1G T-type calcium channels. Circ Res. 2006;98(11):1422-30.
• Abd El-Rahman RR, Harraz OF, Brett SE, Anfinogenova Y, Mufti RE, Goldman D et al. Identification of L- and T-type Ca2+ channels in rat cerebral arteries: role in myogenic tone development. Am J Physiol Heart Circ Physiol. 2013;304(1):H58-71.
• Hansen PB. Functional and pharmacological consequences of the distribution of voltage-gated calcium channels in the renal blood vessels. Acta Physiol (Oxf). 2013;207(4):690-9.
• Hansen PB, Poulsen CB, Walter S, Marcussen N, Cribbs LL, Skøtt O et al. Functional importance of L- and P/Q-type voltage-gated calcium channels in human renal vasculature. Hypertension. 2011;58(3):464-70.
• Gilbert G, Courtois A, Dubois M, Cussac LA, Ducret T, Lory P et al. T-type voltage gated calcium channels are involved in endothelium-dependent relaxation of mice pulmonary artery. Biochem Pharmacol. 2017;138:61-72.