Effects of Melatonin at Different Doses on Experimental Epilepsy Model Induced By Pentylenetetrazole

Year 2021, Volume: 22 Issue: 2, 177 - 186, 31.08.2021

Ferhat Şirinyıldız , Rauf Onur Ek

https://doi.org/10.4274/meandros.galenos.2021.49358

Cited By: 2

Abstract

Objective: This study aimed to evaluate the effect of melatonin (MEL) treatment on rats with experimental epilepsy induced by pentylenetetrazole (PTZ). Changes in the control, epilepsy and two treatment groups (25 mg/kg and 100 mg/kg) were monitored as intragroup and intergroup changes.
Materials and Methods: Forty male Wistar albino rats (12-14 weeks old) were divided into control, PTZ, MEL25 and MEL100 groups, with 10 rats in each group. Only solvent was injected in the control group, and PTZ at a dose of 35 mg/kg was administered intraperitoneal 12 times in a total of 23 days in the PTZ group. MEL25 and 100 mg/kg were administered in the MEL25 and MEL100 groups, respectively. Parameters tested during and after the experiment were behavioural tests (elevated plus maze), biochemical tests in brain tissue [after decapitation; malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), total antioxidant status (TAS) and total oxidant status (TOS)] and epileptic seizure severity scale scores (every injection day).
Results: Significant differences were observed among the epilepsy, control and treatment groups, except for the hiding times, seizure scores and biochemical tests (p<0.05). As a result of biochemical tests applied to the homogenised brain tissue after decapitation, dose-dependent results were found to be related to the different doses of MEL applied in MDA, CAT, SOD, TAS and TOS levels (p<0.05).
Conclusion: In this study, MEL showed a protective and healing role against physiological changes caused by experimental epilepsy, through its capacity to reduce oxidative damage and increase antioxidant potency.

Keywords

Antioxidant , experimental epilepsy , melatonin , oxidative stress , PTZ , rat

References

• 1. Robinson SJ. Childhood epilepsy and autism spectrum disorders: psychiatric problems, phenotypic expression, and anticonvulsants. Neuropsychol Rev 2012; 22: 271-9.
• 2. Ma Y, Sun X, Li J, Jia R, Yuan F, Wei D, et al. Melatonin Alleviates the Epilepsy-Associated Impairments in Hippocampal LTP and Spatial Learning Through Rescue of Surface GluR2 Expression at Hippocampal CA1 Synapses. Neurochem Res 2017; 42: 1438-48.
• 3. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol 2003; 16: 165-70.
• 4. Mosińska P, Socała K, Nieoczym D, Laudon M, Storr M, Fichna J, et al. Anticonvulsant activity of melatonin, but not melatonin receptor agonists Neu-P11 and Neu-P67, in mice. Behav Brain Res 2016; 307: 199-207.
• 5. Gupta YK, Gupta M, Kohli K. Neuroprotective role of melatonin in oxidative stress vulnerable brain. Indian J Physiol Pharmacol 2003; 47: 373-86.
• 6. Frantz AL, Regner GG, Pflüger P, Coelho VR, da Silva LL, Viau CM, et al. Manual acupuncture improves parameters associated with oxidative stress and inflammation in PTZ-induced kindling in mice. Neurosci Lett 2017; 661: 33-40.
• 7. Bambal G, Çakıl D, Ekici F. Models of experimental epilepsy. J Clin Exp Invest 2011; 2: 118-23.
• 8. Löscher W, Hönack D, Fassbender CP, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models. Epilepsy Res 1991; 8: 171-89.
• 9. André V, Pineau N, Motte JE, Marescaux C, Nehlig A. Mapping of neuronal networks underlying generalized seizures induced by increasing doses of pentylenetetrazol in the immature and adult rat: a c-Fos immunohistochemical study. Eur J Neurosci 1998; 10: 2094-106.
• 10. Nasir SA, Sharma A, Khanam R, Vohora D. Effect of medroxyprogesterone on development of pentylenetetrazole-induced kindling in mice. Neuroscience 2012; 207: 283-7.
• 11. Bonnefont-Rousselot D, Collin F. Melatonin: action as antioxidant and potential applications in human disease and aging. Toxicology 2010; 278: 55-67.
• 12. Yamamoto H, Tang HW. Preventive effect of melatonin against cyanide-induced seizures and lipid peroxidation in mice. Neurosci Lett 1996; 207: 89-92.
• 13. Mevissen M, Ebert U. Anticonvulsant effects of melatonin in amygdala-kindled rats. Neurosci Lett 1998; 257: 13-6.
• 14. Borowicz KK, Kamiński R, Gasior M, Kleinrok Z, Czuczwar SJ. Influence of melatonin upon the protective action of conventional anti-epileptic drugs against maximal electroshock in mice. Eur Neuropsychopharmacol 1999; 9: 185-90.
• 15. Uyanikgil Y, Özkeşkek K, Çavuşoğlu T, Solmaz V, Tümer MK, Erbas O. Positive effects of ceftriaxone on pentylenetetrazol-induced convulsion model in rats. Int J Neurosci 2016; 126: 70-5.
• 16. Yeleswaram K, McLaughlin LG, Knipe JO, Schabdach D. Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications. J Pineal Res 1997; 22: 45-51.
• 17. Ying SW, Rusak B, Delagrange P, Mocaer E, Renard P, Guardiola-Lemaitre B. Melatonin analogues as agonists and antagonists in the circadian system and other brain areas. Eur J Pharmacol 1996; 296: 33-42.
• 18. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972; 32: 281-94.
• 19. Pellow S, Chopin P, File SE, Briley M. Validation of open\:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985; 14: 149-67.
• 20. Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2007; 2: 322-8.
• 21. Akdağ M, Akdağ MZ, Daşdağ S, Erel Ö. Oxidative and antioxidative responses in submandibular and parotid glands of rats exposed to long-term extremely low frequency magnetic field. J Clin Exp Invest 2014; 5: 219-25.
• 22. Demougeot C, Marie C, Beley A. Importance of iron location in iron-induced hydroxyl radical production by brain slices. Life Sci 2000; 67: 399-410.
• 23. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988; 34: 497-500.
• 24. Maehly AC, Chance B. The assay of catalases and peroxidases. Methods Biochem Anal 1954; 1: 357-424.
• 25. Hoffman GE, Moore N, Fiskum G, Murphy AZ. Ovarian steroid modulation of seizure severity and hippocampal cell death after kainic acid treatment. Exp Neurol 2003; 182: 124-34.
• 26. McIntyre DC, Racine RJ. Kindling mechanisms: current progress on an experimental epilepsy model. Prog Neurobiol 1986; 27: 1-12.
• 27. Schwartzkroin PA. (Ed.). Epilepsy: models, mechanisms and concepts. 1st Edition. Cambridge University Press 2007.
• 28. Wada T, Fukuda N. Effects of DN-2327, a new anxiolytic, diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze. Psychopharmacology (Berl) 1991; 104: 444-50.
• 29. Yildirim M, Marangoz C. Anticonvulsant effects of melatonin on penicillin-induced epileptiform activity in rats. Brain Res 2006; 1099: 183-8.
• 30. Petkova Z, Tchekalarova J, Pechlivanova D, Moyanova S, Kortenska L, Mitreva R, et al. Treatment with melatonin after status epilepticus attenuates seizure activity and neuronal damage but does not prevent the disturbance in diurnal rhythms and behavioral alterations in spontaneously hypertensive rats in kainate model of temporal lobe epilepsy. Epilepsy Behav 2014; 31: 198-208.
• 31. Choopankareh S, Vafaee F, Shafei MN, Sadeghnia HR, Salarinia R, Zarepoor L, et al. Effects of melatonin and theanine administration on pentylenetetrazole-induced seizures and brain tissue oxidative damage in ovariectomized rats. Turk J Med Sci 2015; 45: 842-9.
• 32. Rodrigues AD, Scheffel TB, Scola G, Santos MT, Fank B, de Freitas SC, et al. Neuroprotective and anticonvulsant effects of organic and conventional purple grape juices on seizures in Wistar rats induced by pentylenetetrazole. Neurochem Int 2012; 60: 799-805.
• 33. Reilly C, Agnew R, Neville BG. Depression and anxiety in childhood epilepsy: a review. Seizure 2011; 20: 589-97.
• 34. Bai J, Cederbaum AI. Mitochondrial catalase and oxidative injury. Biol Signals Recept 2001; 10: 189-99.
• 35. Sudha K, Rao AV, Rao A. Oxidative stress and antioxidants in epilepsy. Clin Chim Acta 2001; 303: 19-24.
• 36. Eun JP, Choi HY, Kwak YG. Proteomic analysis of human cerebral cortex in epileptic patients. Exp Mol Med 2004; 36: 185-91.
• 37. Chang SJ, Yu BC. Mitochondrial matters of the brain: mitochondrial dysfunction and oxidative status in epilepsy. J Bioenerg Biomembr 2010; 42: 457-9.
• 38. Devi PU, Manocha A, Vohora D. Seizures, antiepileptics, antioxidants and oxidative stress: an insight for researchers. Expert Opin Pharmacother 2008; 9: 3169-77.
• 39. Oruc S, Gönül Y, Tunay K, Oruc OA, Bozkurt MF, Karavelioğlu E, et al. The antioxidant and antiapoptotic effects of crocin pretreatment on global cerebral ischemia reperfusion injury induced by four vessels occlusion in rats. Life Sci 2016; 154: 79-86.
• 40. Koksal M, Oğuz E, Baba F, Eren MA, Ciftci H, Demir ME, et al. Effects of melatonin on testis histology, oxidative stress and spermatogenesis after experimental testis ischemia-reperfusion in rats. Eur Rev Med Pharmacol Sci 2012; 16: 582-8.