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Current Drug Therapy

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ISSN (Print): 1574-8855
ISSN (Online): 2212-3903

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Research Article

The Anticonvulsant Activity of Thiamine, Vitamin D3, and Melatonin Combination on Pentylenetetrazole-induced Seizures in Mice

Author(s): Saeed Mehrzadi, Ehsan Dehdashtian, Mohammad Yahya Karimi and Azam Hosseinzadeh*

Volume 17, Issue 4, 2022

Published on: 15 July, 2022

Page: [281 - 288] Pages: 8

DOI: 10.2174/1574885517666220531104009

Price: $65

Abstract

Objective: Epilepsy is a neurological disorder associated with the elevation of oxidative stress levels and alteration in vitamins and endogenous antioxidant levels. The current study was designed to evaluate the effects of Vit D3, thiamine, melatonin, and their combination on pentylenetetrazol (PTZ)-induced tonic-clonic seizures in mice along with measuring the alteration in oxidative stress markers.

Methods: Male mice were randomly divided into seven groups; group I received normal saline (0.5 ml, i.p.) on the 15th day, group II received PTZ (60 mg/kg, i.p) on the 15th day, groups III-VI received diazepam (4 mg/kg), Vit D3 (6000 IU/kg, p.o.), thiamine (200 mg/kg, p.o.), and melatonin (20 mg/kg, p.o.), respectively, before PTZ (60 mg/kg, i.p.) injection on the 15th day, and group VII received the combination of Vit D3, thiamine, and melatonin, before PTZ injection on the 15th day. After PTZ injection, the seizure latency and duration were measured. The malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were evaluated in mice brains.

Results: In the treatment group, the seizure latency was greater and the seizure duration was lower than in the PTZ group. These agents decreased the MDA level and increased SOD activity compared to the PTZ group. The combination of these agents was more effective than each alone to increase seizure latency and reduce seizure duration.

Conclusion: The combination of Vit D3, thiamine, and melatonin could improve PTZ-induced seizures more effectively than each one alone; this may be mediated by inhibiting oxidative stress and regulating various mechanisms involved in seizures.

Keywords: Seizures, pharmacology, melatonin, thiamine, vitamin D3, oxidative stress.

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[1]
Stafstrom CE, Carmant L. Seizures and epilepsy: An overview for neuroscientists. Cold Spring Harb Perspect Med 2015; 5(6): a022426.
[http://dx.doi.org/10.1101/cshperspect.a022426] [PMID: 26033084]
[2]
Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology 2017; 88(3): 296-303.
[http://dx.doi.org/10.1212/WNL.0000000000003509] [PMID: 27986877]
[3]
de Lima Rosa G, Muller Guzzo E, Muliterno Domingues A, Bremm Padilha R, Dias de Oliveira Amaral V, Simon Coitinho A. Effects of prednisolone on behavioral and inflammatory profile in animal model of PTZ-induced seizure. Neurosci Lett 2021; 743: 135560.
[http://dx.doi.org/10.1016/j.neulet.2020.135560] [PMID: 33359047]
[4]
Mehrzadi S, Sadr S, Hosseinzadeh A, et al. Anticonvulsant activity of the ethanolic extract of Punica granatum L. seed. Neurol Res 2015; 37(6): 470-5.
[http://dx.doi.org/10.1179/1743132814Y.0000000460] [PMID: 25413687]
[5]
Homayoun M, Shafieian R, Seghatoleslam M, Hosseini M, Ebrahimzadeh-Bideskan A. Protective impact of Rosa damascena against neural damage in a rat model of pentylenetetrazole (PTZ)-induced seizure. Avicenna J Phytomed 2020; 10(6): 574-83.
[PMID: 33299814]
[6]
Borowicz-Reutt KK, Czuczwar SJ. Role of oxidative stress in epileptogenesis and potential implications for therapy. Pharmacol Rep 2020; 72(5): 1218-26.
[http://dx.doi.org/10.1007/s43440-020-00143-w] [PMID: 32865811]
[7]
Menon B, Ramalingam K, Kumar RV. Low plasma antioxidant status in patients with epilepsy and the role of antiepileptic drugs on oxidative stress. Ann Indian Acad Neurol 2014; 17(4): 398-404.
[http://dx.doi.org/10.4103/0972-2327.144008] [PMID: 25506160]
[8]
Roganovic M, Pantovic S, Dizdarevic S. Role of the oxidative stress in the pathogenesis of epilepsy. Neurol Sci Neurophysiol 2019; 36(1): 1-8.
[9]
Schmidt D. Efficacy of new antiepileptic drugs. Epilepsy Curr 2011; 11(1): 9-11.
[http://dx.doi.org/10.5698/1535-7511-11.1.9] [PMID: 21461260]
[10]
Juybari KB, Hosseinzadeh A, Ghaznavi H, et al. Melatonin as a modulator of degenerative and regenerative signaling pathways in injured retinal ganglion cells. Curr Pharm Des 2019; 25(28): 3057-73.
[http://dx.doi.org/10.2174/1381612825666190829151314] [PMID: 31465274]
[11]
Shahriari M, Mehrzadi S, Naseripour M, et al. Beneficial effects of melatonin and atorvastatin on retinopathy in streptozocin-induced diabetic rats. Curr Drug Ther 2020; 15(4): 396-403.
[http://dx.doi.org/10.2174/1574885514666191204104925]
[12]
Fatemi I, Dehdashtian E, Pourhanifeh MH, Mehrzadi S, Hosseinzadeh A. Therapeutic application of melatonin in the treatment of melanoma: A review. Curr Cancer Ther Rev 2021; 17(4): 283-91.
[http://dx.doi.org/10.2174/1573394717666210526140950]
[13]
Pourhanifeh MH, Kamali M, Mehrzadi S, Hosseinzadeh A. Melatonin and neuroblastoma: A novel therapeutic approach. Mol Biol Rep 2021; 48(5): 4659-65.
[http://dx.doi.org/10.1007/s11033-021-06439-1] [PMID: 34061325]
[14]
Mehrzadi S, Karimi MY, Fatemi A, Reiter RJ, Hosseinzadeh A. SARS-CoV-2 and other coronaviruses negatively influence mitochondrial quality control: Beneficial effects of melatonin. Pharmacol Ther 2021; 224: 107825.
[http://dx.doi.org/10.1016/j.pharmthera.2021.107825] [PMID: 33662449]
[15]
Pourhanifeh MH, Dehdashtian E, Hosseinzadeh A, Sezavar SH, Mehrzadi S. Clinical application of melatonin in the treatment of cardiovascular diseases: Current evidence and new insights into the cardioprotective and cardiotherapeutic properties. Cardiovasc Drugs Ther 2022; 36(1): 131-55.
[PMID: 32926271]
[16]
Pourhanifeh MH, Mehrzadi S, Kamali M, Hosseinzadeh A. Melatonin and gastrointestinal cancers: Current evidence based on underlying signaling pathways. Eur J Pharmacol 2020; 886: 173471.
[http://dx.doi.org/10.1016/j.ejphar.2020.173471] [PMID: 32877658]
[17]
Pourhanifeh MH, Mehrzadi S, Hosseinzadeh A. Melatonin and regulation of miRNAs: Novel targeted therapy for cancerous and noncancerous disease. Epigenomics 2021; 13(1): 65-81.
[http://dx.doi.org/10.2217/epi-2020-0241] [PMID: 33350862]
[18]
Mehrzadi S, Pourhanifeh MH, Mirzaei A, Moradian F, Hosseinzadeh A. An updated review of mechanistic potentials of melatonin against cancer: Pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Cancer Cell Int 2021; 21(1): 188.
[http://dx.doi.org/10.1186/s12935-021-01892-1] [PMID: 33789681]
[19]
Hemati K, Pourhanifeh MH, Fatemi I, Hosseinzadeh A, Mehrzadi S. Anti-degenerative effect of melatonin on intervertebral disc: Protective contribution against inflammation, oxidative stress, apoptosis, and autophagy. Curr Drug Targets 2022.
[http://dx.doi.org/10.2174/1389450123666220114151654] [PMID: 35034592]
[20]
Dabak O, Altun D, Arslan M, et al. Evaluation of plasma melatonin levels in children with afebrile and febrile seizures. Pediatr Neurol 2016; 57: 51-5.
[http://dx.doi.org/10.1016/j.pediatrneurol.2015.12.025] [PMID: 26851993]
[21]
Moezi L, Shafaroodi H, Hojati A, Dehpour AR. The interaction of melatonin and agmatine on pentylenetetrazole-induced seizure threshold in mice. Epilepsy Behav 2011; 22(2): 200-6.
[http://dx.doi.org/10.1016/j.yebeh.2011.07.002] [PMID: 21840768]
[22]
Wilson RB. Pathophysiology, prevention, and treatment of beriberi after gastric surgery. Nutr Rev 2020; 78(12): 1015-29.
[http://dx.doi.org/10.1093/nutrit/nuaa004] [PMID: 32388553]
[23]
Mesdaghinia A, Alinejad M, Abed A, Heydari A, Banafshe HR. Anticonvulsant effects of thiamine on pentylenetetrazole-induced seizure in mice. Nutr Neurosci 2019; 22(3): 165-73.
[http://dx.doi.org/10.1080/1028415X.2017.1357919] [PMID: 28766407]
[24]
Kalueff AV, Minasyan A, Tuohimaa P. Anticonvulsant effects of 1,25-dihydroxyvitamin D in chemically induced seizures in mice. Brain Res Bull 2005; 67(1-2): 156-60.
[http://dx.doi.org/10.1016/j.brainresbull.2005.06.022] [PMID: 16140175]
[25]
Holló A, Clemens Z, Lakatos P. Epilepsy and vitamin D. Int J Neurosci 2014; 124(6): 387-93.
[http://dx.doi.org/10.3109/00207454.2013.847836] [PMID: 24063762]
[26]
Şahin S, Gürgen SG, Yazar U, et al. Vitamin D protects against hippocampal apoptosis related with seizures induced by kainic acid and pentylenetetrazol in rats. Epilepsy Res 2019; 149: 107-16.
[http://dx.doi.org/10.1016/j.eplepsyres.2018.12.005] [PMID: 30584976]
[27]
Institute of Laboratory Animal R. Committee on C. Use of Laboratory A, National Institutes of H, Division of Research R. In: Guide for the Care and Use of Laboratory Animals. Bethesda, Md.: U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health 1985.
[28]
Holló A, Clemens Z, Kamondi A, Lakatos P, Szűcs A. Correction of vitamin D deficiency improves seizure control in epilepsy: A pilot study. Epilepsy Behav 2012; 24(1): 131-3.
[http://dx.doi.org/10.1016/j.yebeh.2012.03.011]
[29]
Pendo K, DeGiorgio CM. Vitamin D3 for the treatment of epilepsy: Basic mechanisms, animal models, and clinical trials. Front Neurol 2016; 7: 218.
[http://dx.doi.org/10.3389/fneur.2016.00218] [PMID: 28008324]
[30]
Kalueff AV, Minasyan A, Keisala T, Kuuslahti M, Miettinen S, Tuohimaa P. Increased severity of chemically induced seizures in mice with partially deleted vitamin D receptor gene. Neurosci Lett 2006; 394(1): 69-73.
[http://dx.doi.org/10.1016/j.neulet.2005.10.007] [PMID: 16256271]
[31]
Rauca C, Wiswedel I, Zerbe R, Keilhoff G, Krug M. The role of superoxide dismutase and α-tocopherol in the development of seizures and kindling induced by pentylenetetrazol - influence of the radical scavenger α-phenyl-N-tert-butyl nitrone. Brain Res 2004; 1009(1-2): 203-12.
[http://dx.doi.org/10.1016/j.brainres.2004.01.082] [PMID: 15120598]
[32]
Fattal-Valevski A, Bloch-Mimouni A, Kivity S, et al. Epilepsy in children with infantile thiamine deficiency. Neurology 2009; 73(11): 828-33.
[http://dx.doi.org/10.1212/WNL.0b013e3181b121f5] [PMID: 19571254]
[33]
McLain AL, Szweda PA, Szweda LI. α-Ketoglutarate dehydrogenase: A mitochondrial redox sensor. Free Radic Res 2011; 45(1): 29-36.
[http://dx.doi.org/10.3109/10715762.2010.534163] [PMID: 21110783]
[34]
Dodd PR, Thomas GJ, McCloskey A, Crane DI, Smith ID. The neurochemical pathology of thiamine deficiency: GABAA and glutamateNMDA receptor binding sites in a goat model. Metab Brain Dis 1996; 11(1): 39-54.
[http://dx.doi.org/10.1007/BF02080930] [PMID: 8815389]
[35]
Taskiran AS, Ergul M. The modulator action of thiamine against pentylenetetrazole-induced seizures, apoptosis, nitric oxide, and oxidative stress in rats and SH-SY5Y neuronal cell line. Chem Biol Interact 2021; 340: 109447.
[http://dx.doi.org/10.1016/j.cbi.2021.109447] [PMID: 33771525]
[36]
Peled N, Shorer Z, Peled E, Pillar G. Melatonin effect on seizures in children with severe neurologic deficit disorders. Epilepsia 2001; 42(9): 1208-10.
[http://dx.doi.org/10.1046/j.1528-1157.2001.28100.x] [PMID: 11580772]
[37]
Mohammadi F, Shakiba S, Mehrzadi S, Afshari K, Rahimnia AH, Dehpour AR. Anticonvulsant effect of melatonin through ATP-sensitive channels in mice. Fundam Clin Pharmacol 2020; 34(1): 148-55.
[http://dx.doi.org/10.1111/fcp.12490] [PMID: 31197879]
[38]
Goldberg-Stern H, Oren H, Peled N, Garty B-Z. Effect of melatonin on seizure frequency in intractable epilepsy: A pilot study. J Child Neurol 2012; 27(12): 1524-8.
[http://dx.doi.org/10.1177/0883073811435916] [PMID: 22378657]
[39]
Mohanan PV, Yamamoto HA. Preventive effect of melatonin against brain mitochondria DNA damage, lipid peroxidation and seizures induced by kainic acid. Toxicol Lett 2002; 129(1-2): 99-105.
[http://dx.doi.org/10.1016/S0378-4274(01)00475-1] [PMID: 11879979]
[40]
Bikjdaouene L, Escames G, León J, et al. Changes in brain amino acids and nitric oxide after melatonin administration in rats with pentylenetetrazole-induced seizures. J Pineal Res 2003; 35(1): 54-60.
[http://dx.doi.org/10.1034/j.1600-079X.2003.00055.x] [PMID: 12823614]
[41]
León J, Macías M, Escames G, et al. Structure-related inhibition of calmodulin-dependent neuronal nitric-oxide synthase activity by melatonin and synthetic kynurenines. Mol Pharmacol 2000; 58(5): 967-75.
[http://dx.doi.org/10.1124/mol.58.5.967] [PMID: 11040043]
[42]
Muñoz-Hoyos A, Molina-Carballo A, Macías M, et al. Comparison between tryptophan methoxyindole and kynurenine metabolic pathways in normal and preterm neonates and in neonates with acute fetal distress. Eur J Endocrinol 1998; 139(1): 89-95.
[http://dx.doi.org/10.1530/eje.0.1390089] [PMID: 9703384]
[43]
Hemati K, Pourhanifeh MH, Dehdashtian E, et al. Melatonin and morphine: Potential beneficial effects of co-use. Fundam Clin Pharmacol 2021; 35(1): 25-39.
[http://dx.doi.org/10.1111/fcp.12566] [PMID: 32415694]
[44]
Gül SS, Aygün H. Cardioprotective effect of vitamin D and melatonin on doxorubicin-induced cardiotoxicity in rat model: An electrocardiographic, scintigraphic and biochemical study. Eur Res J 2019; 5(4): 649-57.
[45]
Sahakyan G. The role of vitamin d in treatment of chronic insomnia with melatonin (P5. 320) AAN Enterprises 2018.
[46]
Alamro AA, Al-Malky MM, Ansari MGA, et al. The effects of melatonin and vitamin D3 on the gene expression of BCl-2 and BAX in MCF-7 breast cancer cell line. J King Saud Univ Sci 2021; 33(2): 101287.
[http://dx.doi.org/10.1016/j.jksus.2020.101287]
[47]
Proietti S, Cucina A, D’Anselmi F, et al. Melatonin and vitamin D3 synergistically down-regulate Akt and MDM2 leading to TGFβ-1-dependent growth inhibition of breast cancer cells. J Pineal Res 2011; 50(2): 150-8.
[PMID: 21091766]
[48]
Özerkan D, Özsoy N, Yılmaz E. Vitamin D and melatonin protect the cell’s viability and ameliorate the CCl4 induced cytotoxicity in HepG2 and Hep3B hepatoma cell lines. Cytotechnology 2015; 67(6): 995-1002.
[http://dx.doi.org/10.1007/s10616-014-9738-8] [PMID: 24997582]
[49]
Martín Giménez VM, Inserra F, Tajer CD, et al. Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment. Life Sci 2020; 254: 117808.
[http://dx.doi.org/10.1016/j.lfs.2020.117808] [PMID: 32422305]
[50]
Fang N, Hu C, Sun W, et al. Identification of a novel melatonin-binding nuclear receptor: Vitamin D receptor. J Pineal Res 2020; 68(1): e12618.
[http://dx.doi.org/10.1111/jpi.12618] [PMID: 31631405]
[51]
Mocayar Marón FJ, Ferder L, Reiter RJ, Manucha W. Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin. J Steroid Biochem Mol Biol 2020; 199: 105595.
[http://dx.doi.org/10.1016/j.jsbmb.2020.105595] [PMID: 31954766]
[52]
Dehdashtian E, Hosseinzadeh A, Hemati K, Karimi MY, Fatemi I, Mehrzadi S. Anti-convulsive effect of thiamine and melatonin combination in mice: Involvement of oxidative stress. Cent Nerv Syst Agents Med Chem 2021; 21(2): 125-9.
[http://dx.doi.org/10.2174/1871524921666210623161212] [PMID: 34165417]
[53]
Sharma A, Bist R, Bubber P. Thiamine deficiency induces oxidative stress in brain mitochondria of Mus musculus. J Physiol Biochem 2013; 69(3): 539-46.
[http://dx.doi.org/10.1007/s13105-013-0242-y] [PMID: 23417786]
[54]
Mkrtchyan GV, Üçal M, Müllebner A, et al. Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex. Biochim Biophys Acta Bioenerg 2018; 1859(9): 925-31.
[http://dx.doi.org/10.1016/j.bbabio.2018.05.005] [PMID: 29777685]
[55]
Gangolf M, Wins P, Thiry M, El Moualij B, Bettendorff L. Thiamine triphosphate synthesis in rat brain occurs in mitochondria and is coupled to the respiratory chain. J Biol Chem 2010; 285(1): 583-94.
[http://dx.doi.org/10.1074/jbc.M109.054379] [PMID: 19906644]

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