Sıçanlarda Pentilentetrazol İle İndüklenen Akut ve Kronik Epilepsi Modellerinde Thymus vulgaris L.’nin Etkileri
Bu çalışmanın amacı pentilentetrazol ile indüklenen akut ve kronik epilepsi modellerinde Thymus vulgaris L. (TVL)’in oksidatif stres, motor koordinasyon ve öğrenme/bellek üzerine etkilerini araştırmaktır. Bu amaçla 64 adet Wistar albino sıçan randomize olarak sekiz gruba ayrıldı. (1) akut kontrol (AC), (2) akut pentilentetrazol (APTZ) (3) akut PTZ + sodyum valproat (APTZ+VPA), (4) akut PTZ +TVL (APTZ+TVL), (5) kronik kontrol (CC), (6) PTZ tutuşma (PTZk), (7) PTZ tutuşma + VPA (PTZk+VPA) ve (8) PTZ tutuşma + TVL (PTZk + TVL). PTZ enjeksiyonundan sonra 30 dk boyunca nöbetler gözlenerek skorlandı. Çalışmada tek doz PTZ (60 mg/kg, ip) enjeksiyonu ile akut PTZ indüklü nöbet modeli oluşturuldu. Tutuşma ise gün aşırı subkonvulsan dozda PTZ (35 mg/kg, ip) uygulanarak toplam 14 enjeksiyonla oluşturuldu. PTZk+VPA, PTZk ve PTZk+TVL grupları arasında nöbet skorları bakımından anlamlı bir fark bulunamadı. Kronik çalışma gruplarında Morris water maze cihazı ile yapılan öğrenme ve bellek testleri yanında rota rod cihazı ile yapılan motor aktivite testlerinde gruplar arasında farklılık görülmedi (P>0.05). Total antioksidan statüsü (TAS), total oksidan statüsü (TOS) ve oksidatif stres indeksi (OSİ) sonuçları, PTZ uygulaması neticesinde antioksidan kapasitenin azaldığı, oksidan kapasitenin ise arttığı belirlendi. T. vulgaris’in özellikle uzun süre uygulanması ile total oksidanantioksidan dengenin sağlandığı görüldü. Sonuç olarak gelecekte, daha yüksek dozlarda T. vulgaris L.’nin PTZ indüklü nöbet skorlarını değiştirip değiştirmeyeceğini belirlenmesi için ek çalışmaların yapılabileceği düşünülmektedir.
Effects of Thymus vulgaris L. in Acute and Chronic Epilepsy Models in Rats Induced by Pentylenetetrazole
The aim of this study was to investigate the effects of Thymus vulgaris L. (TVL) on oxidative stress, motor coordination and learning/memory in acute and chronic epilepsy models in rats induced by Pentylenetetrazole (PTZ). To this end, 64 male Wistar-albino rats were randomly divided into eight groups with 8 rats each: (1) acute control (AC), (2) acute PTZ (APTZ), (3) acute PTZ + sodium valproate (APTZ+VPA), (4) acute PTZ + TVL (APTZ+TVL), (5) chronic control (CC), (6) PTZ kindling (PTZk), (7) PTZ kindling + VPA (PTZk+VPA) and (8) PTZ kindling + TVL (PTZk+TVL) . Seizures were observed for 30 min after each PTZ injection and were scored. Acute PTZ-induced seizures were created by injecting a single convulsive dose of PTZ (60 mg/kg, ip) in acute groups. PTZ kindling was produced by injecting a subconvulsant dose of PTZ (35 mg/kg, ip) every other day, with 14 injections in total. No significant difference was found among the PTZk + VPA, PTZk, and PTZk + TVL groups with regard to seizure scores. No significant difference was found among all the 8 groups in the learning/memory tests conducted using the Morris Water Maze (MWM) test and the motor activity tests conducted using the rotarod test (P>0.05). The analysis of total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) indicated that the administration of PTZ decreased the antioxidant capacity and increased the oxidant capacity. Moreover, the TVL administration established the oxidant/antioxidant balance, particularly in the chronic groups. Further studies are needed to investigate whether high doses of TVL have an effect on PTZ-induced seizure scores.
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- 1. Pitkanen A, Sutula TP: Is epilepsy a progressive disorder? Prospects for new therapeutic approaches in temporal lobe epilepsy. Lancet Neurol, 1 (3): 173-181, 2002. DOI: 10.1016/S1474-4422(02)00073-X
- 2. Altıntaş A: Nöroinflamasyon, İmmun Mekanizmalar ve Epilepsi. Türk Farmakoloji Derneği 22. Ulusal Farmakoloji Kongresi. 4-7 Kasım, Antalya, Bildiri Özet Kitabı: 35-36, 2013.
- 3. Löscher W: Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Res, 50 (1-2): 105-123, 2002. DOI: 10.1016/S09201211(02)00073-6
- 4. Onat F: Antiepileptik ilaç hedefi olarak İnflamasyon. Türk Farmakoloji Derneği 22. Ulusal Farmakoloji Kongresi. 4-7 Kasım, Antalya, Bildiri Özet Kitabı: 37-38, 2013.
- 5. Akarsu E: Sistematik inflamatuar yanıt ve nöronal eksitabilite. Türk Farmakoloji Derneği 22. Ulusal Farmakoloji Kongresi. 4-7 Kasım, Antalya, Bildiri Özet Kitabı: 39-40, 2013.
- 6. Vezzani A, Bartfai T, Bianchi M, Rossetti C, French J: Therapeutic potential of new antiinflammatory drugs. Epilepsia, 52 (S8): 67–69, 2011. DOI: 10.1111/j.1528-1167.2011.03242.x
- 7. Baytop T, Başer KHC, Kırımer N: Türkiye’de Bitkilerle Tedavi. İstanbul Üniversitesi, Eczacılık Fakültesi Yayınları, No. 3255. İstanbul Bitkisel İlaç Hammaddeleri Toplantısı, Bildiriler, 29-31 Mayıs 2002, Eskişehir, 434-457, 1984.
- 8. Özcan M, Chalchat JC: Aroma profile of Thymus vulgaris L. Growing wild in Turkey. Bulg J Plant Physiol, 30 (3-4): 68-73, 2004.
- 9. Gençaslan G: Türkiye’de Tıbbi Amaçlı Kullanılan Bazı Bitkilerin Antioksidan Etkilerinin Taranması. Yüksek Lisans Tezi, Ankara Üniv. Sağlık Bil. Enst., 2007.
- 10. Fakıllı O, Özgüven M: Inventory of researches on thyme (Thymus vulgaris L) in Turkey. ÇÜ Fen Mühendislik Bil Derg, 27 (3): 54-66, 2012.
- 11. Prasanth RV, Ravi Vital K, Varsha P, Satyan S: Review on Thymus vulgaris traditional uses and pharmacological properties. Med Aromat Plants, 3 (3): 164-167, 2014. DOI: 10.4172/2167-0412.1000164
- 12. Akkol EK, Avci G, Kucukkurt I, Keles H, Tamer U, Ince S, Yesilada E: Cholesterol-reducer, antioxidant and liver protective effects of Thymbra spicata L. var. spicata. J Ethnopharmacol, 126, 314-319, 2009. DOI: 10.1016/ j.jep.2009.08.020
- 13. Koparal AT, Zeytinoğlu M: Effects of carvacrol on a human non-small cell lung cancer (NSCLC) cell line A549. Cytotechnolog, 43, 149-154, 2003.
- 14. Dikilidal M: STZ ile diyabet oluşturulmuş ratlarda kekik (Thymus vulgaris L.) ve karabaş kekiğinin (Thymbra spicata L.) kan glikoz düzeyine, kilo değişikliğine ve öğrenmeye etkisi. Yüksek Lisans Tezi, Van YYÜ Sağlık Bil. Enst., 2013.
- 15. Manoharan S, Guillemin GJ, Abiramasundari RS, Essa MM, Akbar M, Akbar MD: Role of reactive oxygen species in the pathogenesis of alzheimer’s disease,parkinson’s disease, and huntington’s disease: A mini review. Oxid Med Cell Longev, 2016:8590578, 2016. DOI: 10.1155/ 2016/8590578
- 16. Ali BH, Blunden G: Pharmacological and toxicological properties of Nigella sativa. Phytother Res, 17, 299-305, 2003. DOI: 10.1002/ptr.1309
- 17. Eddouks M, Maghrani M, Zeggwagh NA, Michel J: Study of the hypoglycaemic activity of Lepidium sativum L. aqueous extract in normal and diabetic rats, J Ethnopharmacol, 97, 391-395, 2005. DOI: 10.1016/j. jep.2004.11.030
- 18. Patsoukis N, Zervoudakis G, Panagopoulos N, Georgiou CD, Angelatou F, Matsokis NA: Thiol redox state (TRS) and oxidative stress in the mouse hippocampus after pentylenetetrazol-induced epileptic seizure. Neurosci Lett, 357 (2): 83-86, 2004. DOI: 10.1016/j.neulet.2003.10.080
- 19. Ilhan A, Iraz M, Kamisli S, Yigitoglu R: Pentylenetetrazol-induced kindling seizure attenuated by Ginkgo biloba extract (EGb 761) in mice. Prog Neuropsychopharmacol Biol Psychiatry, 30 (8): 1504-1510, 2006. DOI: 10.1016/j.pnpbp.2006.05.013
- 20. Racine RJ: Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 32, 281–294, 1972. DOI: 10.1016/0013-4694(72)90177-0
- 21. Rajabzadeh A, Bideskan AE, Fazel A, Sankian M, Rafatpanah H, Haghir H: The effect of PTZ-induced epileptic seizures on hippocampal expression of PSA-NCAM in offspring born to kindled rats. J Biomed Sci, 19:56, 2012. DOI: 10.1186/1423-0127-19-56
- 22. Morris RGM, Garrud P, Rawlins JNP, O’Keefe J: Place navigation impaired in rats with hippocampal lesions. Nature, 297, 681-683, 1982. DOI: 10.1038/297681a0
- 23. Terry AV: Spatial Navigation (Water Maze) Tasks. In, Buccafusco JJ (Ed): Source Methods of Behavior Analysis in Neuroscience. 2nd ed., Chapter 13, 153-166, Boca Raton (FL): CRC Press/Taylor & Francis, 2009.
- 24. Tuzcu M, Baydas G: Effect of melatonin and vitamin E on diabetesinduced learning and memory impairment in rats. Eur J Pharmacol, 537 (13): 106-110, 2006. DOI: 10.1016/j.ejphar.2006.03.024
- 25. Erel O: A new automated coloremetric method for measuring total oxidant status. Clin Biochem, 38, 1103-1111, 2005. DOI: 10.1016/j.clinbiochem. 2005.08.008
- 26. Kurt M, Çelik S, Kesim Y: Motor eşgüdümde dopaminerjik sistemin rolü. OMÜ Tıp Derg, 19, 15-24, 2002.
- 27. Pearson-Smith JN, Patel M: Metabolic dysfunction and oxidative stress in epilepsy. Int J Mol Sci, 18 (11): pii:E2365, 2017. DOI: 10.3390/ ijms18112365
- 28. Aguiar CCT, Almeida AB, Araujo PVP, de Abreu RNDC, Chaves EMC, do Vale OC, Macêdo DS, Woods DJ, Fonteles MM, Vasconcelos SMM: Oxidative stress and epilepsy: Literature review. Oxid Med Cell Longev, 2012:795259, 2012. DOI: 10.1155/2012/795259
- 29. Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR: Estimation of the burden of active and lifetime epilepsy: a metaanalytic approach. Epilepsia, 51 (5): 883-890, 2010. DOI: 10.1111/j.15281167.2009.02481.x
- 30. Rabiei Z: Anticonvulsant effects of medicinal plants with emphasis on mechanisms of action. Asian Pac J Trop Biomed, 7 (2): 166-172, 2017. DOI: 10.1016/j.apjtb.2016.11.028
- 31. Birben E, Sahiner U, Sackesen C, Erzurum S, Kalayci O: Oxidative stress and antioxidant defense. World Allergy Organ J, 5 (1): 270, 2012.
- 32. Li G, Bauer S, Nowak M, Norwood B, Tackenberg B, Rosenow F, Knake S, Oertel WH, Hamer HM: Cytokines and epilepsy. Seizure, 20 (3): 249-256, 2011. DOI: 10.1016/j.seizure.2010.12.005
- 33. Ergül Erkeç O, Arihan O: Pentylenetetrazol kindling epilepsy model. Epilepsi, 21 (1): 6-12, 2015. DOI: 10.5505/epilepsi.2015.08108
- 34. Martinc B, Grabnar I, Vovk T: The role of reactive species in epileptogenesis and influence of antiepileptic drug therapy on oxidative stress. Curr Neuropharmacol, 10 (4): 328-343, 2012.
- 35. Kong Q, Lin CLG: Oxidative damage to RNA: Mechanisms, consequences, and diseases. Cell Mol Life Sci, 67 (11): 1817-1829, 2010. DOI: 10.1007/ s00018-010-0277-y
- 36. Lan J, Henshall DC, Simon RP, Chen J: Formation of the base modification 8-hydroxyl-2’-deoxyguanosine and DNA fragmentation following seizures induced by systemic kainic acid in the rat. J Neurochem, 74, 302309, 2000. DOI: 10.1046/j.1471-4159.2000.0740302.x
- 37. Tan D, Manchester LC, Reiter RJ, Qi W, Kim SJ, El-Sokkary GH: Melatonin protects hippocampal neurons in vivo against kainic acidinduced damage in mice. J Neurosci Res, 54, 382–389, 1998. DOI: 10.1002/ (SICI)1097-4547(19981101)54:3<382::AID-JNR9>3.0.CO;2-Y
- 38.Gupta RC, Milatovic D, Zivin M, Dettbarn WD: Seizure-induced changes in energy metabolites and effects of N-tert-butyl-alpha-phenylnitrone (PNB) and vitamin E in rats. Eur J Physiol, 440, R160-R162, 2000. DOI: 10.1007/ s004240000047
- 39. Aboul Ezz HS, Khadrawy YA, Noor NA: The neuroprotective effect of curcumin and Nigella sativa oil against oxidative stress in the pilocarpine model of epilepsy: A comparison with valproate. Neurochem Res, 36 (11): 2195-204, 2011. DOI: 10.1007/s11064-011-0544-9
- 40. Taiwe GS, Moto FCO, Ayissi ERM, Ngoupaye GT, Njapdounke JSK, Nkantchoua GCN, Kouemou N, Omam JPO, Kandeda AK, Pale S, Pahaye D, Ngobum E: Effects of a lyophilized aqueous extract of Feretia apodanthera Del. (Rubiaceae) on pentylenetetrazole-induced kindling, oxidative stress, and cognitive impairment in mice. Epilepsy Behav, 43, 100108, 2015. DOI: 10.1016/j.yebeh.2014.11.022
- 41. Rathor N, Arora T, Manocha S, Patil AM, Mediratta P, Sharma KK: Anticonvulsant activity of Aloe vera leaf extract in acute and chronic models of epilepsy in mice. J Pharm Pharmacol, 66 (3): 477-485, 2014. DOI: 10.1111/ jphp.12181
- 42. Addaea JI, Pingal R, Walkins K, Cruickshank R, Youssef FF, Nayak SB: Effects of Jasminum multiflorum leaf extract on rodent models of epilepsy, motor coordination and anxiety. Epilepsy Res, 131, 58-63, 2011. DOI: 10.1016/j.eplepsyres.2017.02.012
- 43. Kandeda AK, Taiwe GS, Moto FCO, Ngoupaye GT, Nkantchoua GCN, Njapdounke JSK, Omam JPO, Pale S, Kouemou N, Ngo Bum EN: Antiepileptogenic and neuroprotective effects of Pergularia daemia on pilocarpine model of epilepsy. Front Pharmacol, 8:440, 2017. DOI: 10.3389/ fphar.2017.00440
- 44. Zhen J, Chang Y, Qu Z, Fu T, Liu J, Wang W: Luteolin rescues pentylenetetrazole-induced cognitive impairment in epileptic rats by reducing oxidative stress and activating PKA/CREB/BDNF signaling. Epilepsy Behav, 57, 177-184, 2016. DOI: 10.1016/j.yebeh.2016.02.001
- 45. Skalicka-Woźniak K, Walasek M, Aljarba TM, Stapleton P, Gibbons S, Xiao J, Łuszczki J: The anticonvulsant and anti-plasmid conjugation potential of Thymus vulgaris chemistry: An in vivo murine and in vitro study. Food Chem Toxicol, 120, 472-478, 2018. DOI: 10.1016/j.fct.2018.07.045
- 46. Okay Tİ, Kısa C, Dilbaz N: Psikiyatrik bozukluklarda valproat kullanımı. Klinik Psikiyatri, 5, 33-41, 2002.
- 47. Abdelgadir AB, El- Hadiyah TMH: Assessment of the anticonvulsant effect of Thymus vulgaris plant. 2017. http://mmacpanel.delta.edu.sd/ includes/magazines/pdf/1_6_7.pdf; Accessed: 28.01.2019.
- 48. Gao B, Wu Y, Yang Y, Li W, Dong K, Zhou J, Yin Y, Huang DK, Wu WN: Sinomenine exerts anticonvulsant profile and neuroprotective activity in pentylenetetrazole kindled rats: Involvement of inhibition of NLRP1 inflammasome. J Neuroinflammation, 15:152, 2018. DOI: 10.1186/s12974018-1199-0
- 49. Kaur H, Patro I, Tikoo K, Sandhir R: Curcumin attenuates inflammatory response and cognitive deficits in experimental model of chronic epilepsy: Neurochem Int, 89, 40-50, 2015. DOI: 10.1016/j.neuint.2015.07.009
- 50. Eddy CM, Rickards HE, Cavanna AE: The cognitive impact of antiepileptic drugs. Ther Adv Neurol Disord, 4, 385-407, 2011. DOI: 10.1177/ 1756285611417920
- 51. Morteza-Semnani K, Mahmoudi M, Riahi G: Effects of essential oils and extracts from certain Thymus. Species on swimming performance in mice. Pharm Biol, 45 (6): 464-467, 2007. DOI: 10.1080/13880200701389177
- 52. Akan Z, Dikilidal M, Özdemir H, Oto G, Yilmaz A: Effects of Thymus vulgaris L. and Thymbra spicata L. on diabetes mellitus associated cognitive impairment and neuropathy: Thymus vulgaris and cognitive function improvements. Med Sci Discov, 1 (1): 16-21, 2014.
- 53. Hamm RJ, Pike BR, O›Dell DM, Lyeth BG, Jenkins LW: The rotarod test: An evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma, 11 (2): 187-96, 1994. DOI: 10.1089/ neu.1994.11.187