Therapeutic effect of acute and chronic use of different doses of vitamin D3 on seizure responses and cognitive impairments induced by pentylenetetrazole in immature male rats

Document Type : Original Article

Authors

1 Department of Pediatric, Weinan Maternal and Child Health Hospital, Weinan, 714000, China

2 Department of Child Health, Weinan Central Hospital, Weinan, 714000, China

Abstract

Objective(s): This study aimed to evaluate the effects of acute and chronic intake of different doses of vitamin D3 on seizure responses and cognitive impairment induced by pentylenetetrazole (PTZ) in immature male rats.
Materials and Methods: Sixty-six immature male NMRI rats were divided into control (10), epileptic (10), and treatment groups (46). The stage 5 latency (S5L) and stage 5 duration (S5D) were assessed along with the shuttle box test. Levels of antioxidant enzymes and inflammatory factors along with genes involved in inflammation, oxidative damage, apoptosis, and mTORc1 were measured in the hippocampus tissue of the brain of controlled and treated rats. Serum levels of parathyroid hormone (PTH), vitamin D, calcium, and phosphorus were also assessed.
Results: The results showed that the ability to learn, memory consolidation, and memory retention in epileptic rats were reduced. In addition, S5D increased and S5L decreased in epileptic rats, while being effectively ameliorated by chronic and acute vitamin D intake. The results showed that vitamin D in different doses acutely and chronically decreased the levels of oxidative and inflammatory biomarkers in hippocampus tissue and inhibited the expression of genes involved in inflammation, oxidative damage, apoptosis, and mTORc1 in the hippocampus tissue of epileptic rats. 
Conclusion: The results showed that vitamin D in different doses acutely and chronically could improve cognitive impairments and convulsive responses in epileptic rats by improving neurotransmission, inflammation, apoptosis, and oxidative damage.

Keywords


1. Cebeci AN, Ekici B. Epilepsy treatment by sacrificing vitamin D. Expert Review Neurother 2014; 14:481-491. 
2. WHO. WHO global report on epilepsy. World Health Organization. 2019. 
3. Amza A, editor Global health: epilepsy. In Seminars in neurology; 2018 2018: Thieme Medical Publishers. 
4. Operto FF, Pastorino GMG, Mazza R, Carotenuto M, Roccella M, Marotta R, et al. Effects on executive functions of antiepileptic monotherapy in pediatric age. Epilepsy Behav 2020; 102:106648-106654. 
5. Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med 2015; 5:22426-22444. 
6. Sudha K, Rao AV, Rao A. Oxidative stress and antioxidants in epilepsy. Clin Chim Acta 2001; 303:19-24. 
7. Ambrogini P, Torquato P, Bartolini D, Albertini MC, Lattanzi D, Di Palma M, et al. Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: the role of vitamin E. Biochim Biophy Acta Mol Basis Dis 2019; 1865:1098-1112. 
8. Bagla S, Dombkowski AA. Neuroinflammatory nexus of pediatric epilepsy. J Pediatr epilepsy 2018; 7:32-39. 
9. Méndez-Armenta M, Nava-Ruíz C, Juárez-Rebollar D, Rodríguez-Martínez E, Yescas Gómez P. Oxidative stress associated with neuronal apoptosis in experimental models of epilepsy. Oxid Medicine Cell Longev 2014;  :293689-293701. 
10. Rojas A, Chen D, Ganesh T, Varvel NH, Dingledine R. The COX-2/prostanoid signaling cascades in seizure disorders. Expert opinion on therapeutic targets 2019;23(1):1-13. 
11. Xiao Z, Peng J, Gan N, Arafat A, Yin F. Interleukin- 1β plays a pivotal role via the PI3K/Akt/mTOR signaling pathway in the chronicity of mesial temporal lobe epilepsy. Neuroimmunomodulation 2016; 23:332-344. 
12. Sultan S, Taimuri U, Basnan SA, Ai-Orabi WK, Awadallah A, Almowald F, et al. Low vitamin D and its association with cognitive impairment and dementia. J Aging Res 2020; :6097820-6097830. 
13. Teagarden DL, Meador KJ, Loring DW. Low vitamin D levels are common in patients with epilepsy. Epilepsy Res 2014; 108:1352-1356. 
14. Clemens Z, Holló A, Kelemen A, Rásonyi G, Fabó D, Halász P, et al. Seasonality in epileptic seizures. J Neurol Transl Neurosci 2013; 1:1016-1019. 
15. Roth DE, Abrams SA, Aloia J, Bergeron G, Bourassa MW, Brown KH, et al. Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low- and middle-income countries. Ann N Y Acad Sci 2018; 1430:44-79. 
16. Lenck-Santini P-P, Scott RC. Mechanisms responsible for cognitive impairment in epilepsy. Cold Spring Harb Perspect Med 2015; 5:22772-22787. 
17. Junges C, Machado TD, Nunes PRS, Riesgo R, Mello EDd. Vitamin D deficiency in pediatric patients using antiepileptic drugs: systematic review with meta-analysis. J Pediatr 2020; 96:559-568. 
18. Yazdi SAM, Abbasi M, Yazdi SMM. Epilepsy and vitamin D: a comprehensive review of current knowledge. Rev Neurosci 2017; 28:185-201. 
19. Groves NJ, Burne THJ. The impact of vitamin D deficiency on neurogenesis in the adult brain. Neural Regen Res 2017; 12:393- 394. 
20. Breitling LP, Perna L, Müller H, Raum E, Kliegel M, Brenner H. Vitamin D and cognitive functioning in the elderly population in Germany. Exp Gerontol 2012; 47:122-127. 
21. 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; 24:131-133.
22.    Lauer AA, Janitschke D, Hartmann T, Grimm HS, Grimm MOW. The effects of vitamin D deficiency on neurodegenerative diseases. In:  Vitam D Deficiency. IntechOpen. 3th ed. Homburg/Saar, Germany: Saarland University; 2019:125-150.
23.    Pendo K, DeGiorgio CM. Vitamin D3 for the treatment of epilepsy: basic mechanisms, animal models, and clinical trials. Front Neurol 2016; 7:218-224.
24.    Kalueff AV, Minasyan A, Tuohimaa P. Anticonvulsant effects of 1, 25-dihydroxyvitamin D in chemically induced seizures in mice. Brain Res Bull 2005; 67:156-160.
25.    Palizvan MR, Fathollahi Y, Semnanian S, Hajezadeh S, Mirnajafizadh J. Differential effects of pentylenetetrazol-kindling on long-term potentiation of population excitatory postsynaptic potentials and population spikes in the CA1 region of rat hippocampus. Brain Res 2001; 898:82-90.
26.    Rauca C, Pohle W, Grunenberg K, Franze S. Hypothermia inhibits pentylenetetrazol kindling and prevents kindling-induced deficit in shuttle-box avoidance. Pharmacol Biochem Behav 2000; 65:23-30.
27.    Esterbauer H, Cheeseman KH. Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal.  Methods Enzymol 1990; 186:407-421.
28.    Fukuzawa K, Tokumurai A. Glutathione peroxidase activity in tissues of vitamin E-deficient mice. J Nutr Sci Vitaminol 1976; 22:405-407.
29.    Genet S, Kale RK, Baquer NZ. Alterations in antioxidant enzymes and oxidative damage in experimental diabetic rat tissues: effect of vanadate and fenugreek (Trigonella foenum graecum). Mol Cell Biochem 2002; 236:7-12.
30.    Aebi H. Catalase. In: Methods of enzymatic analysis. Bergmeyer HU. Elsevier; 1974:673-684.
31.    Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Sci 1973; 179:588-590.
32.    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 2001; 25:402-408.
33.    Mahmoudi T, Lorigooini Z, Rafieian-Kopaei M, Arabi M, Rabiei Z, Bijad E, et al. Effect of Curcuma zedoaria hydro-alcoholic extract on learning, memory deficits and oxidative damage of brain tissue following seizures induced by pentylenetetrazole in rat. Behav Brain Funct 2020; 16:1-12.
34.    Shimada T, Yamagata K. Pentylenetetrazole-induced kindling mouse model. J Vis Exp 2018; 136:56573-56583.
35.    Yuan X, Fu Z, Ji P, Guo L, Al-Ghamdy AO, Alkandiri A, et al. Selenium nanoparticles pre-treatment reverse behavioral, oxidative damage, neuronal loss and neurochemical alterations in pentylenetetrazole-induced epileptic seizures in mice. Int J Nanomedicine 2020; 15:6339-6353.
36.    Hamadi N, Sheikh A, Madjid N, Lubbad L, Amir N, Shehab SA-DS, et al. Increased pro-inflammatory cytokines, glial activation and oxidative stress in the hippocampus after short-term bilateral adrenalectomy. BMC Neurosci 2016; 17:1-18.
37.    Engel T, Henshall DC. Apoptosis, Bcl-2 family proteins and caspases: the ABCs of seizure-damage and epileptogenesis? Int J Physiol Pathophysiol Pharmacol 2009; 1:97-115.
38.    Shi Y, Zhang L, Teng J, Miao W. HMGB1 mediates microglia activation via the TLR4/NF-κB pathway in coriaria lactone induced epilepsy. Mol Med Rep 2018; 17:5125-5131.
39.    Paudel YN, Shaikh M, Chakraborti A, Kumari Y, Aledo-Serrano Á, Aleksovska K, et al. HMGB1: a common biomarker and potential target for TBI, neuroinflammation, epilepsy, and cognitive dysfunction. Front Neurosci 2018; 12:628-647.
40.    Xiao Z, Peng J, Wu L, Arafat A, Yin F. The effect of IL-1β on synaptophysin expression and electrophysiology of hippocampal neurons through the PI3K/Akt/mTOR signaling pathway in a rat model of mesial temporal lobe epilepsy. Neurol Res 2017; 39:640-648.
41.    Streicher KL, Willmarth NE, Garcia J, Boerner JL, Dewey TG, Ethier SP. Activation of a nuclear factor κB/interleukin-1 positive feedback loop by amphiregulin in human breast cancer cells. Mol Cancer Res 2007; 5:847-861.
42.    Vezzani A, Baram TZ. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy Curr 2007; 7:45-50.
43.    Xiao Z, Peng J, Yang L, Kong H, Yin F. Interleukin-1β plays a role in the pathogenesis of mesial temporal lobe epilepsy through the PI3K/Akt/mTOR signaling pathway in hippocampal neurons. J Neuroimmunol 2015; 282:110-117.
44.    Steinbrecher KA, Wilson W, 3rd, Cogswell PC, Baldwin AS. Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription. Mol Cell Biol 2005; 25:8444-8455.
45.    Mattson MP, Camandola S. NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 2001; 107:247-254.
46.    Al Khalifah R, Hudairi A, Al Homyani D, Hamad MH, Bashiri FA. Vitamin D supplementation to prevent vitamin D deficiency for children with epilepsy: randomized pragmatic trial protocol. Med 2018; 97:12734-12739.
47.    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; 394:69-73.
48.    Hii CS, Ferrante A. The non-genomic actions of vitamin D. Nutrients 2016; 8:135-149.
49.    Norman AW. Vitamin D receptor: new assignments for an already busy receptor. Endocrinol 2006; 147:5542-5548.
50.    Janjoppi L, Katayama MH, Scorza FA, Folgueira MAAK, Brentani M, Pansani AP, et al. Expression of vitamin D receptor mRNA in the hippocampal formation of rats submitted to a model of temporal lobe epilepsy induced by pilocarpine. Brain Res Bull 2008; 76:480-484.
51.    Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Europ J Immunol 2006; 36:361-370.
52.    Farhangi MA, Mesgari-Abbasi M, Hajiluian G, Nameni G, Shahabi P. Adipose tissue inflammation and oxidative stress: the ameliorative effects of vitamin D. Inflammation 2017; 40:1688-1697.
53.    Zhang H, Yang N, Wang T, Dai B, Shang Y. Vitamin D reduces inflammatory response in asthmatic mice through HMGB1/TLR4/NFκB signaling pathway. Mol Med Rep 2018; 17:2915-2920.
54.    Kim MS, Lee S, Jung N, Lee K, Choi J, Kim S-H, et al. The vitamin D analogue paricalcitol attenuates hepatic ischemia/reperfusion injury through down-regulation of toll-like receptor 4 signaling in rats. Arch Med Sci 2017; 13:459-569.
55.    Lisse TS, Hewison M. Vitamin D. Cell Cycle 2011; 10:1888-1889.
56.    Lisse TS, Liu T, Irmler M, Beckers J, Chen H, Adams JS, et al. Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling. FASEB J 2011; 25:937-947.
57.    Eyles DW. Vitamin D: Brain and behavior. JBMR Plus 2020; 5:10419-10431.
58.    Shirazi HA, Rasouli J, Ciric B, Rostami A, Zhang G-X. 1, 25-dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation. Exp Mol Pathol 2015; 98:240-245.
59.    Araque A, Navarrete M. Glial cells in neuronal network function. Philos Trans R Soc Biol Sci 2010; 365:2375-2381.
60. da Silva Teixeira S, Harrison K, Uzodike M, Rajapakshe K, Coarfa C, He Y, et al. Vitamin D actions in neurons require the PI3K pathway for both enhancing insulin signaling and rapid depolarizing effects. J Steroid Biochem Mol Biol 2020; 200:105690-105709.