PTZ kindling modeli: Ramelteon'un etkisi altında EEG faktörü ve biyokimya parametrelerinin değerlendirilmesi

Year 2024, Volume: 12 Issue: 3, 843 - 859, 21.10.2024

Mukaddes Pala , Ramazan Kozan , Hayrullah Köse , Şenay Görücü Yılmaz

https://doi.org/10.33715/inonusaglik.1495324

Abstract

Pek çok seçici sentetik melatonin reseptörü agonisti, antikonvülsan/anti-epileptojenik özelliklere sahiptir. Bu agonistler melatonin reseptörü 1 (MT1) ve melatonin reseptörü 2'ye (MT2) bağlanarak onların aktivasyonlarına neden olmaktadır. Bu nedenle, bir melatonin agonisti olarak Ramelteon'un (RMLT) antikonvülsan etkisini PTZ (Pentilenetetrazol)-kindling modelinde değerlendirdik. Çalışmada 36 adet erkek Wistar Albino sıçan grupta (Sham, PTZ, dimetilsülfoksit (DMSO), Valproik asit (VPA) (150 mg/kg) + PTZ, RMLT (30 mg/kg)+PTZ, VPA+RMLT+PTZ) değerlendirildi. Tüm gruplar için kortikal elektroensefalografi (EEG) verileri kaydedildi. Nöbetler Racine skalasına göre skorlandı. EEG traselerinde nöbet skorları ve ilk miyoklonik hareketlerin başlangıç zamanları karşılaştırıldı. Serum örneklerinde toplam antioksidan durum (TAS), toplam oksidan durum (TOS), katalaz, miyeloperoksidaz (MPO) ve Tiyol seviyeleri ölçüldü. Ayrıca beyin dokusu örneklerinde Kalsinörin (CaN), Nöropeptid-Y (NPY), Nöron Spesifik Enolaz (NSE) ve S100B seviyeleri ölçüldü. PTZ ve PTZ+Valproik asit+RMLT grupları arasında Racine'in konvülsiyon evrelerinde ilk miyoklonik hareketlerin başlangıcı ve EEG traselerindeki ani artış oranları açısından anlamlı bir fark vardı (P<0.001). Biyokimyasal parametreler, gruplar arasında anlamlı değildi (P > 0.05). RMLT antikonvülsan özelliklere sahiptir. Ek olarak RMLT'nin reseptör tercihi de araştırılabilir.

Keywords

Antikonvülsan etki, Elektroensefalografi, Epilepsi, Pentilentetrazol, Ramelteon

Project Number

12.2011/15

PTZ KINDLING MODEL: EVALUATION OF EEG FACTOR AND BIOCHEMISTRY PARAMETERS UNDER THE INFLUENCE OF RAMELTEON

Abstract

Many selective synthetic melatonin receptor agonists have anticonvulsant/anti-epileptogenic properties. These agonists bind to melatonin receptor 1 (MT1) and receptor 2 (MT2), causing their activation. Therefore, we evaluated the anticonvulsant effect of Ramelteon (RMLT) as a melatonin agonist in the PTZ (Pentylenetetrazol)-kindling model. In the study, 36 male Wistar Albino rats were assessed in 6 groups (Sham, PTZ, dimethylsulphoxide (DMSO), Valproic acid (VPA) (150 mg/kg) + PTZ, RMLT (30 mg/kg)+PTZ, VPA+RMLT+PTZ). Cortical electroencephalography (EEG) data were recorded for all groups. Seizures were scored according to the Racine scale. Seizure scores and onset times of the first myoclonic movements were compared in EEG traces. Total antioxidant status (TAS), total oxidant status (TOS), catalase, myeloperoxidase (MPO), and Thiol levels were measured in serum samples. Also, Calcineurin (CaN), Neuropeptide-Y (NPY), Neuron Specific Enolase (NSE), and S100B levels were measured in brain tissue samples. There was a significant difference between the PTZ and PTZ+Valproic acid+RMLT groups for the onset of the first myoclonic movements and the rate of spikes in the EEG traces in Racine's convulsion stages (P<0.001). Biochemical parameters were not significant between the groups (P > 0.05). RMLT has anticonvulsant properties. Additionally, the receptor preference of RMLT can be investigated.

Keywords

Anticonvulsant effect, Electroencephalography, Epilepsy, Pentylenetetrazole, Ramelteon

Ethical Statement

Study permission was obtained from Bezmialem Vakif University Experimental Animals Local Ethics Committee (2011/51).

Supporting Institution

Bezmialem Vakıf Üniversitesi

Project Number

12.2011/15

References

• Aebi, H. (1984). Catalase in vitro. Methods Enzymol, 105, 121-126.
• Altıparmak, I. H., Erkuş, M. E., Sezen, H., Demirbag, R., Gunebakmaz, O., Kaya, Z., Neselioglu, S. (2016). The relation of serum thiol levels and thiol/disulphide homeostasis with the severity of coronary artery disease. Kardiologia Polska (Polish Heart Journal), 74(11), 1346-1353.
• Arhan, E., Kurt, A. N. C., Neselioglu, S., Yerel, O., Uçar, H. K., Aydin, K. & Serdaroglu, A. (2019). Effects of antiepileptic drugs on dynamic thiol/disulphide homeostasis in children with idiopathic epilepsy. Seizure, 65, 89-93.
• Aslankoc, R., Savran, M., Doğuç, D. K., Sevimli, M., Tekin, H. & Kaynak, M. (2022). Ameliorating effects of ramelteon on oxidative stress, inflammation, apoptosis, and autophagy markers in methotrexate-induced cerebral toxicity. Iranian journal of basic medical sciences, 25(10), 1183–1189.
• Bai, M., Cai, X., Li, Z., Huang, L., Gu, C., Li, Y., Jia, Z. (2018). Clinical value of serum S100B in children with epilepsy. Int. J. Clin. Exp. Med, 11(12), 13535-13540.
• Baraban, S. (2004). Neuropeptide Y and epilepsy: recent progress, prospects and controversies. Neuropeptides, 38(4), 261-265.
• Beltrán-Sarmiento, E., Arregoitia-Sarabia, C. K., Floriano-Sánchez, E., Sandoval-Pacheco, R., Galván-Hernández, D. E., Coballase-Urrutia, E., Cárdenas-Rodríguez, N. (2018). Effects of valproate monotherapy on the oxidant-antioxidant status in Mexican epileptic children: a longitudinal study. Oxidative medicine and cellular longevity, 2018.
• Bergstrom, R. A., Choi, J. H., Manduca, A., Shin, H.-S., Worrell, G. A. & Howe, C. L. (2013). Automated identification of multiple seizure-related and interictal epileptiform event types in the EEG of mice. Scientific Reports, 3(1), 1483.
• Blumenfeld, H. (2012). Impaired consciousness in epilepsy. The Lancet Neurology, 11(9), 814-826.
• Bradley, P. P., Priebat, D. A., Christensen, R. D. & Rothstein, G. (1982). Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. Journal of Investigative Dermatology, 78(3), 206-209.
• Colmers, W. F. & Bahh, B. E. (2003). Neuropeptide Y and epilepsy. Epilepsy Currents, 3(2), 53-58.
• Dell'Isola, G. B., Tascini, G., Vinti, V., Tulli, E., Dini, G., Mencaroni, E., Verrotti, A. (2023). Effect of melatonin on sleep quality and EEG features in childhood epilepsy: a possible non-conventional treatment. Frontiers in neurology, 14, 1243917.
• Drexel, M. & Sperk, G. (2022). Seizure-induced overexpression of NPY induces epileptic tolerance in a mouse model of spontaneous recurrent seizures. Frontiers in Molecular Neuroscience, 15, 974784.
• Ellman G.L. (1959). Tissue sulfhydryl groups. Arch Biochem Biophys, 82(1), 70-77.
• Erel, O. (2004). A novel automated method to measure total antioxidant response against potent free radical reactions. Clinical biochemistry, 37(2), 112-119.
• Erel, O. (2005). A new automated colorimetric method for measuring total oxidant status. Clinical biochemistry, 38(12), 1103-1111.
• Fenoglio-Simeone, K., Mazarati, A., Sefidvash-Hockley, S., Shin, D., Wilke, J., Milligan, H., Maganti, R. (2009). Anticonvulsant effects of the selective melatonin receptor agonist ramelteon. Epilepsy & Behavior, 16(1), 52-57.
• Herman, S. (2006). Acute Seizures and Status Epilepticus. Handbook of Neuroemergency Clinical Trials, 81-124.
• Hu, M.-L. (1994). Measurement of protein thiol groups and glutathione in plasma. In Methods in enzymology (Vol. 233, pp. 380-385): Elsevier.
• Isgrò, M. A., Bottoni, P. & Scatena, R. (2015). Neuron-specific enolase as a biomarker: biochemical and clinical aspects. Advances in cancer biomarkers: from biochemistry to clinic for a critical revision, 125-143.
• Johannessen CU, J. S. (2003). Valproate: past, present, and future. CNS Drug Rev, 9(2),199-216.
• Kaputlu, İ. & Uzbay, T. (1997). L-NAME inhibits pentylenetetrazole and strychnine-induced seizures in mice. Brain research, 753(1), 98-101.
• Khan, S., Khurana, M., Vyas, P. & Vohora, D. (2021). The role of melatonin and its analogues in epilepsy. Reviews in the Neurosciences, 32(1), 49-67.
• Kösem, A., Yücel, Ç., Titiz, A. P., Sezer, S., Neşelioğlu, S., Erel, Ö. & Turhan, T. (2021). Evaluation of serum thiol-disulphide homeostasis parameters as oxidative stress markers in epilepsy patients. Acta Neurologica Belgica, 121, 1555-1559.
• Liang, K.-G., Mu, R.-Z., Liu, Y., Jiang, D., Jia, T.-T. & Huang, Y.-J. (2019). Increased serum S100B levels in patients with epilepsy: a systematic review and meta-analysis study. Frontiers in neuroscience, 13, 456.
• Liu, M., Ding, J. & Wang, X. (2022). The interaction between circadian rhythm and epilepsy. Acta Epileptologica, 4(1), 28.
• Löscher, W. (2002a). Current status and future directions in the pharmacotherapy of epilepsy. Trends in pharmacological sciences, 23(3), 113-118.
• Löscher, W. (2002b). Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 16, 669-94.
• Rao, V.R. & Lowenstein, D.H. (2022). Seizures and epilepsy. Loscalzo J, & Fauci A, & Kasper D, & Hauser S, & Longo D, & Jameson J(Eds.), Harrison's Principles of Internal Medicine, 21e. McGraw-Hill Education.
• Mahomoodally, M. F. & MA-L, E. R. (2022). Catalase. In Antioxidants Effects in Health (pp. 81-90), Elsevier.
• Millichap, J. G. (2010). Melatonin and Intractable Epilepsy. Pediatric Neurology Briefs, 24(4), 30.
• Miyamoto, M. (2009). Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS neuroscience & therapeutics, 15(1), 32-51.
• Mori N, O. S. (1992 ). Comparison of anticonvulsant effects of valproic acid entrapped in positively and negatively charged liposomes in amygdaloid-kindled rats. Brain Res, 593(2),329-31.
• Pattnaik, A. R., Ghosn, N. J., Ong, I. Z., Revell, A. Y., Ojemann, W. K., Scheid, B. H., Sinha, S. R. (2023). The seizure severity score: a quantitative tool for comparing seizures and their response to therapy. Journal of Neural Engineering, 20(4), 046026.
• Paxinos, G. & Watson, C. (2009). The Rat Brain in Stereotaxic Coordinates: Elsevier/Academic.
• Rogawski, M. A. L. W. (2004). The neurobiology of antiepileptic drugs. Nat Rev Neurosci, 5(7), 553-564.
• Scharfman, H. E. (2007). The neurobiology of epilepsy. Current neurology and neuroscience reports, 7(4), 348-354.
• Sefil F, A. A., Acar MD, Bostancı MÖ, Bagirici F, Kozan R. (2015). Interaction between carbenoxolone and valproic acid on pentylenetetrazole kindling model of epilepsy. Int J Clin Exp Med, 8(7), 10508-14.
• Shaik, A. J., Reddy, K., Mohammed, N., Tandra, S. R. & KSS, S. B. (2019). Neuron specific enolase as a marker of seizure related neuronal injury. Neurochemistry International, 131, 104509.
• Shibasaki, F., Hallin, U. & Uchino, H. (2002). Calcineurin as a multifunctional regulator. The Journal of biochemistry, 131(1), 1-15.
• Souza, M. A., Mota, B. C., Gerbatin, R. R., Rodrigues, F. S., Castro, M., Fighera, M. R. & Royes, L. F. F. (2013). Antioxidant activity elicited by low dose of caffeine attenuates pentylenetetrazol-induced seizures and oxidative damage in rats. Neurochemistry International, 62(6), 821-830.
• Tchekalarova, J., Petkova, Z., Pechlivanova, D., Moyanova, S., Kortenska, L., Mitreva, R., Stoynev, A. (2013). Prophylactic treatment with melatonin after status epilepticus: Effects on epileptogenesis, neuronal damage, and behavioral changes in a kainate model of temporal lobe epilepsy. Epilepsy & Behavior, 27(1), 174-187.
• Terzioglu Bebitoglu B, O. E., Gokce A. (2020). Effect of valproic acid on oxidative stress parameters of glutamate-induced excitotoxicity in SH-SY5Y cells. Exp Ther Med, 20(2),1321-1328.
• Vacas, M. I., Sarmiento, M., Pereyra, E. N., Etchegoyen, G. S. & Cardinali, D. P. (1987). In vitro effect of neuropeptide Y on melatonin and norepinephrine release in rat pineal gland. Cellular and molecular neurobiology, 7(3), 309-315.
• Verma, N., Maiti, R., Mishra, B. R., Jha, M., Jena, M. & Mishra, A. (2021). Effect of add‐on melatonin on seizure outcome, neuronal damage, oxidative stress, and quality of life in generalized epilepsy with generalized onset motor seizures in adults: A randomized controlled trial. Journal of Neuroscience Research, 99(6), 1618-1631.
• Wang, M., Li, S., Zhou, G., Liao, W., Li, G. & Xiao, B. (2012). H-magnetic resonance spectroscopy on bilateral thalamus of patients with secondarily generalized tonic-clonic seizures. Zhong nan da xue xue bao. Yi xue ban= Journal of Central South University. Medical Sciences, 37(11), 1147-1151.
• Wen, Y., Fu, P., Wu, K., Si, K., Xie, Y., Dan, W., Shi, Q. (2017). Inhibition of calcineurin a by FK506 suppresses seizures and reduces the expression of GluN2B in membrane fraction. Neurochemical Research, 42, 2154-2166.
• Xiong, T.-Q., Chen, L.-M., Tan, B.-H., Guo, C.-Y., Li, Y.-N., Zhang, Y.-F., Li, Y.-C. (2018). The effects of calcineurin inhibitor FK506 on actin cytoskeleton, neuronal survival and glial reactions after pilocarpine-induced status epilepticus in mice. Epilepsy Research, 140, 138-147.
• Zammit, G. K. (2007). Ramelteon: a novel hypnotic indicated for the treatment of insomnia. Psychiatry (Edgmont), 4(9), 36.
• Zhang, Y., Seeburg, D. P., Pulli, B., Wojtkiewicz, G. R., Bure, L., Atkinson, W., Zhang, W. (2016). Myeloperoxidase nuclear imaging for epileptogenesis. Radiology, 278(3), 822-830.
• Zhang, Y., Zhang, M., Wang, X., Yu, Y., Jin, P. & Wang, Y. (2011). Effects of sodium valproate on neutrophils' oxidative metabolism and oxidant status in children with idiopathic epilepsy. Zhonghua er ke za zhi= Chinese Journal of Pediatrics, 49(10), 776-781.