Şule BULUR, Şerif DEMİR, ANZEL BAHADIR, SEYİT ANKARALI, RECEP ÖZMERDİVENLİ, ERSİN BEYAZÇİÇEK

The Effects of Erythropoietin on the Penicillin Induced Epileptiform Activity in Rats

Eritropoietin (Epo), böbreklerde sentezlenen ve kemik iliğinde eritrosit üretimini sağlayan bir sitokin hormonudur. Deneysel epilepsi araştırmalarında, genel olarak penisilin ile oluşturulan epilepsi modeli kullanılmaktadır. Çalışmamızda, anestezi altındaki yetişkin WistarAlbino türü sıçanlarda (n=39), Penisilin-G (intrakortikal (i.c) olarak, 500 I.U/2.5 µl dozda) ile oluşturulmuş epileptik aktivite üzerine Epo'nun etkileri araştırıldı. Sıçanlar, üç tedavi grubu ve bir kontrol grubu (ilaç uygulanmadı) olarak rastgele dört farklı gruba ayrıldı. Grup 1, 2 ve 3'de bulunan sıçanlara, intraperitonal olarak sırayla 2.000, 4.000 and 6.000 IU Epo/kg'lık dozlarda Epo uygulandı. Gruplar arasında, penisilin G ile oluşturulan epilepsi üzerine Epo'nun etkisi elektrokortikografi kullanılarak karşılaştırıldı. Kontrol grubu ile Epo grubu karşılaştırıldığında, 4.000 ve 6.000 IU/kg Epo uygulaması, dakika başına diken dalgaların ve dikenlerin ortalama sayısı ve nöbet şiddetini anlamlı (P0.05). Sonuç olarak yapılan çalışma, Epo'nun sıçanlarda penisilin ile oluşturulmuş deneysel epilepsi modeli üzerine uygulanmasının, doz bağımlı antiepileptik etkiye neden olduğu ortaya çıkarmıştır.

Sıçanlarda Penisilin ile Oluşturulan Epileptiform Aktivitesi Üzerine Eritropoietinin Etkileri

Erythropoietin (Epo), a cytokine hormone produced in the kidney, promotes the formation of red blood cells in the bone marrow. The penicillin-induced epilepsy model is a commonly used experimental model for epilepsy research. The present study was conducted to elucidate the effect of Epo on penicillin-G (500 IU/2.5 µl dose, intracortically (i.c)) -induced epileptiform activity in anesthetized adult Wistar-Albino rats (n=39). The animals were randomly divided into four groups as three treatment groups and a control group (no drug application). Rats in groups 1, 2 and 3 were intraperitoneally administered 2.000, 4.000 and 6.000 IU Epo/kg, respectively. The effects on penicillin G induced epilepsy were compared across groups using electrocorticography. Epo at 2.000 IU/kg did not cause a significant change (P>0.05) in epileptiform spike-wave activity (number/min) and/or amplitude (µV) values, whereas the average number of spike-waves per minute and seizure severity decreased significantly in the 4.000 and 6.000 IU/kg Epo groups compared with the control (P<0.05). Consequently, the results of the present study show that administration of Epo has a dosedependent antiepileptic effect in penicillin induced model of epilepsy in rats.

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Scharfman HE: The neurobiology of epilepsy. Curr Neurol Neurosci Rep, 7, 348-354, 2007.
Shneker BF, Fountain NB: Epilepsy. Dis Mon, 49, 426-478, 2003. DOI: 1016/S0011-5029(03)00065-8
Fisher RS: Animal model of the epilepsies. Brain Res Rev, 14, 245-278, Contreras D: Experimental models in epilepsy. Revista de Neurol, 30, 376, 2000.
Garcia Garcia ME, Garcia Morales I, Matías Guiu J: Experimental models in epilepsy. Neurologia, 25, 181-188, 2010. DOI: 10.1016/S2173- (10)70035-3
Bağırıcı F, Gökçe FM, Demir S, Marangoz C: Calcium channel blocker flunarizine suppresses epileptiform activity induced by penicillin in rats. Neurosci Res Com, 28, 135-140, 2001. DOI: 10.1002/nrc.1014
Ayyildiz M, Yildirim M, Agar E, Baltaci AK: The effects of leptin on penicillin induced epileptiform activity in the rats. Brain Res Bulletin, , 374-378, 2006. DOI: 10.1016/j.brainresbull.2005.09.012
Gökçe FM, Bağırıcı F, Demir S, Bostancı MÖ, Güven A: The effect of neuronal nitricoxide synthase inhibitor 7-nitroindazole on the cell death Induced by zinc administration in the brain of rats. Turk J Med Sci, 39, 202, 2009. DOI: 10.3906/sag-0708-13
Yildirim M, Ayyildiz M, Agar E: Endothelial nitric oxide synthase activity involves in the protective effect of ascorbic acid against penicillin- induced epileptiform activity. Seizure, 19, 102-108, 2010. DOI: 10.1016/j. seizure.2009.12.005
Kammerer M, Rassner MP, Freiman TM, Feuerstein TJ: Effects of antiepileptic drugs on GABA release from rat and human neocortical synaptosomes. Naunyn Schmiedeberg's Arch Pharmacol, 384, 47-57, 2011. DOI: 10.1007/s00210-011-0636-8
Loscher W: Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure, 20, 359-368, 2011. DOI: 10.1016/j.seizure.2011.01.003
Jelkmann W: Molecular biology of erythropoietin. Intern Med, 43, 659, 2004.
Genc S, Koroglu TF, Genc K: Erythropoietin and the nervous system. Brain Res, 1000, 19-31, 2004. DOI: 10.2169/internalmedicine.43.649
Nadam J, Navarro F, Sanchez P, Moulin C, Georges B, Laglaine A, Pequignot JM, Morales A, Rylin P, Bezin L: Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus. Neurol Dis, 25, 412-426, 2007. DOI: 10.1016/j.nbd.2006.10.009
Rabie T, Marti HH: Brain protection by erythropoietin: A manifold task. Phsyology (Bethesda), 23, 263-274, 2008. DOI: 10.1152/physiol.00016.2008
Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A: Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci, 97, 10526- 10531, 2000. DOI: 10.1073/pnas.97.19.10526
Uzum G, Diler AS, Bahçekapılı N, Ziylan YZ: Erythropoietin prevents the increase in blood-brain barier permeability during pentylentetrazole induced seizures. Life Sci, 78, 2571-2576, 2006. DOI: 1016/j.lfs.2005.10.027
Kondo A, Shingo T, Yasuhara T, Kuramoto S, Kameda M, Kikuschi Y, Matsui T, Miyoshi Y, Agari T, Borlongan CV, Date I: Erythropoietin exerts anti-epileptic effects with the suppression of aberrant new cell formation in the dentate gyrus and upregulation of neuropeptide Y in sizure model rats. Brain Res, 1296, 127-136, 2009. DOI: 10.1016/j.brainres.2009.08.025
Chu K, Jung KH, Lee ST, Kim JH, Kang KM, Kim HK, Lim JS, Park HK, Kim M, Lee SK, Roh JK: Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia, 49, 1723-1732, 2008. DOI: 10.1111/j.1528-1167.2008.01644.x
Liu XB, Wang JA, Yu SP, Keogh CL, Wei L: Therapeutic strategy of eryhropoetin in neurological disorders. CNS Neurol Disord Drug Tragets, , 227-234, 2008. DOI: 10.2174/187152708784936617
Sargin D, Friedrichs H, El-Kordi A, Ehrenreich H: Erythropoietin as neuroprotective and neuroregenerative treatment startegy: Comprehensive overview of 12 years of preclinical and clinical research. Best Pract Res Clin Anaest, 24, 573-594, 2010. DOI: 10.1016/j. bpa.2010.10.005
Sozmen SC, Hız Kurul S, Yis U, Tugyan K, Baykara B, Yılmaz O: Neuroprotective effects of recombinant human erythroprotein in the developing brain of rat after lithium-pilocarpine induced status epilepticus. Brain Develop, 34, 189-195, 2012. DOI: 10.1016/j. braindev.2011.05.002
Wen X, Huang Y, Wang J: Erythropoietin preconditioning on hippocampus neuronal apoptasis following status epilepticus induced by lithium-pilocarpine in rats through anti-caspase-3 expression. J Neurol India, 54, 58-63, 2006. DOI: 10.4103/0028-3886.24708
Liu X, Shen J, Jin Y, Duan M, Xu J: Recombinant human erythropoietin (rhEPO) preconditioning on nuclear factor-kappa B (NFkB) activation & proinflammatory cytokines induced by myocardial ischaemia-reperfusion. Indian J Med Res, 124, 343-354, 2006.
Akman O, Ozkanlar YE, Ozkanlar S, Oruc E, Ulas N, Ziypak T, Lehimcioglu NC, Turkeli M, Ucar O: Erythropoietin hormone and ACE inhibitor protect the sperm parameters of adult male rats against doxorubicin toxicity. Kafkas Univ Vet Fak Derg, 21, 805-812, 2015. DOI: 9775/kvfd.2015.13412
Genc S, Koroglu TG, Genc K: Erythropoietin as a novel neuro- protectant. Restor Neurol Neurosci, 22 (2) :105-119, 2004.
Eid T, Brines M: Recombinant human erythropoietin for neuro- protection: What is the evidence? Clin Breast Cancer, 3, 109-115, 2002. DOI: 10.3816/CBC.2002.s.021
Yang J, Huang Y, Yu X, Sun H, Li Y, Deng Y: Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. Acta Neurobil Exp, 57, 693-702, 2009.
Sargin D, Hassouna I, Sperling S, Siren AL, Ehrenrich H: Uncoupling of neurodegeneration and gliosis in a murine model of juvenile cortical lesion. Glia, 57, 693-702, 2009. DOI: 10.1002/glia.20797
Won YJ, Yoo JY, Lee JH, Hwang SJ, Kim D, Hong HN: Erythropoietin is neuroprotective on GABAergic neurons against kainic acid- excitotoxicity in the rat spinal cell cultures. Brain Res, 1154, 31-39, 2007. DOI: 10.1016/j. brainres.2007.04.010
Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R: Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience, 76, 105-116, 1997. DOI: 10.1016/S0306-4522(96)00306-5
Gunnarson E, Song Y, Kowalewski JM, Brismar H, Brines M, Cerami A, Andersson U, Zelenina M, Aperia A: Erythropoietin modulation of astrocyte water permeability as a component of neuroprotection. Proc Natl Acad, 106, 1602-1607, 2009. DOI: 10.1073/pnas.0812708106