Author(s):
Ruzanna Paronikyan, Sona Buloyan, Anahit Pogosyan, Lilit Arshakyan, Lilit Mirzoyan, Hrachik Gasparyan
Email(s):
sonabuloyan@gmail.com
DOI:
10.52711/0974-360X.2024.00799 
Address:
Ruzanna Paronikyan, Sona Buloyan*, Anahit Pogosyan, Lilit Arshakyan, Lilit Mirzoyan, Hrachik Gasparyan
Scientific Technological Center of Organic and Pharmaceutical Chemistry,
National Academy of Sciences of the Republic of Armenia, Yerevan, Armenia.
*Corresponding Author
Published In:
Volume - 17,
Issue - 11,
Year - 2024
ABSTRACT:
Epilepsy is considered the most common neurological disease globally, characterized by recurrent unprovoked seizures. The primary treatment for epilepsy involves therapy with antiepileptic drugs to control seizures. However, therapeutic options for this condition are limited, and many of these drugs have various side effects on the central nervous system, leading to cognitive impairment. Therefore, the development of new effective agents with anti-seizure activity and mild side effects remains a significant challenge. In this study, we aimed to investigate the anticonvulsant and neuroprotective activities of several new derivatives of hydantoin, namely (D,L)-5-((1H-Indol-3-yl)methyl)imidazolidine-2,4-dione (ART 2), lithium salt of 5,5-diphenylimidazolidine-2,4-dione (ART 5), lithium salt of (D,L)-5-benzylimidazolidine-2,4-dione (ART 1215), and lithium salt of (D,L)-5-((1H-indol-3-yl)methyl)imidazolidine-2,4-dione (ART 2125). The anticonvulsant properties of these compounds were evaluated using pentylenetetrazol (PTZ) and maximal electroshock seizure (MES) models. Additionally, the neuroprotective activity of the compounds was assessed through histopathological examination of the hippocampus and entorhinal cortex with and without PTZ administration. Our findings indicate that the new derivatives of hydantoin exhibit greater efficacy in treating clonic seizures and have lower toxicity and myorelaxation compared to phenytoin. Among the tested compounds, ART 5 and ART 1215 not only mitigated PTZ-induced damage but also preserved neuronal integrity in the hippocampus and entorhinal cortex, indicating their potent neuroprotective effects.
Cite this article:
Ruzanna Paronikyan, Sona Buloyan, Anahit Pogosyan, Lilit Arshakyan, Lilit Mirzoyan, Hrachik Gasparyan. Evaluating Anticonvulsant and Neuroprotective potentials of New Hydantoin Derivatives in PTZ and MES Models. Research Journal of Pharmacy and Technology. 2024; 17(11):5221-9. doi: 10.52711/0974-360X.2024.00799
Cite(Electronic):
Ruzanna Paronikyan, Sona Buloyan, Anahit Pogosyan, Lilit Arshakyan, Lilit Mirzoyan, Hrachik Gasparyan. Evaluating Anticonvulsant and Neuroprotective potentials of New Hydantoin Derivatives in PTZ and MES Models. Research Journal of Pharmacy and Technology. 2024; 17(11):5221-9. doi: 10.52711/0974-360X.2024.00799 Available on: https://rjptonline.org/AbstractView.aspx?PID=2024-17-11-7
REFERENCES:
1. Beghi E. Giussani G. Aging and the epidemiology of epilepsy. Neuroepidemiology. 2018; 51: 216–23. doi.org/10.1159/000493484.
2. Chen Z. Brodie M. J. Ding D. Kwan, P. Editorial: Epidemiology of epilepsy and seizures. Frontiers in Epidemiology, 2023; 3: 1273163.
3. Milligan TA. Epilepsy: A Clinical Overview, The American Journal of Medicine, 2021; 134(7): 840-7, doi.org/10.1016/j.amjmed.2021.01.038.
4. Poduri A. Lowenstein D. Epilepsy genetics--past, present, and future. CurrOpin Genet Dev. 2011; 21(3): 325-32. doi.org/10.1016/j.gde.2011.01.005.
5. McCance KL. Huether SE.Epilepsy. In Pathophysiology: The Biologic Basis for Disease in Adults and Children. 2014; 678-81, Elsevier Health Sciences
6. Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med. 2015; 1; 5(6): a022426. doi.org/10.1101/cshperspect.a022426.
7. Jain P. Surana A. Pandey R. Shukla ShSh. Epilepsy: A Neurological Cramp. Research J. Pharmacology and Pharmacodynamics. 2013; 5(1): 01-05.
8. Golyala A. Kwan P. Drug development for refractory epilepsy: The past 25 years and beyond. Seizure. 2017; 44: 147-56. doi.org/: 10.1016/j.seizure.2016.11.022.
9. Tamilselvan T. Arokia RC. Ashna R. Leena PM. Nissy V. Sojan PP. Prescription Analysis of Antiepileptic Drugs in a Tertiary Care Hospital. Asian J. Pharm. Tech. 2018; 8(1): 43-6. DOI: 10.5958/2231-5713.2018.00007.7.
10. Zhang Z. Sun T. Niu JG, He ZQ, Liu Y. Wang F. Amentoflavone protects hippocampal neurons: anti-inflammatory, antioxidative, and antiapoptotic effects. Neural Regen Res. 2015; 10(7): 1125-33. doi.org/10.4103/1673-5374.160109.
11. Perucca E. Meador KJ. Adverse effects of antiepileptic drugs. ActaNeurolScand Suppl. 2005; 181: 30-5. doi.org/10.1111/j.1600-0404.2005.00506.x.
12. Bhattacharya R. Chakraborty S. Sanyal D. Bhattacharyya S. Mandal M. Mazumder J. A Unique Case of Ito Syndrome presenting with Juvenile Myoclonic Epilepsy and Normal Intelligence. Asian J. Nur. Edu. and Research 2014;4(4): 417-20.
13. Tatum WO. Use of antiepileptic drugs in pregnancy. Expert Rev Neurother. 2006; 6(7): 1077-86. doi.org/10.1586/14737175.6.7.1077.
14. Chimakurthy J. Murthy TEGK. Upadhyay L.. Effect of Curcumin on Sub-Therapeutic Doses of AED’S And Long Term Memory In MES Induced GTC Type of Seizures in Rats. Research J. Pharm. and Tech. 2008; 1(4): 401-04.
15. Steinhoff BJ. Pregnancy, epilepsy, and anticonvulsants. Dialogues ClinNeurosci. 2008; 10(1): 63-75. doi.org/10.31887/DCNS.2008.10.1/bjsteinhoff.
16. Beerhorst K. van der Kruijs SJ, Verschuure P, Tan IY. Aldenkamp AP. Bone disease during chronic antiepileptic drug therapy: general versus specific risk factors. J Neurol Sci. 2013; 15; 331 (1-2): 19-25. doi.org/10.1016/j.jns.2013.05.005.
17. Patocka J. Wu Q. Nepovimova E, Kuca K. Phenytoin - An anti-seizure drug: Overview of its chemistry, Pharmacology and Toxicology. Food Chem Toxicol. 2020; 142: 111393. doi.org/10.1016/j.fct.2020.111393.
18. Keppel HJM. Kopsky DJ. Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action. J Neurol. 2017; 264(8): 1617-21. doi.org/10.1007/s00415-017-8391-5.
19. Imam SH. Landry K. Kaul V. Gambhir H. John D. Kloss B. Free phenytoin toxicity. Am J Emerg Med. 2014; 32(10): 1301.e3-4. doi.org/10.1016/j.ajem.2014.03.036.
20. Mendem A. Arma M. Mugada V. kiran Kolakota R. A Review on effectiveness of different Antiepileptic Drugs in Pediatric Febrile Seizures. Asian J. Res. Pharm. Sci. 2019; 9(2): 85-90. DOI: 10.5958/2231-5659.2019.00013.4.
21. Rayni I. El Bakri Y. Lai CH. El Ghayati L. Essassi EM. Mague JT. Synthesis, crystal structure, DFT calculations and Hirshfeld surface analysis of 2-(1-decyl-2-oxo-indolin-3-yl-idene)propanedi-nitrile. Acta Crystallogr E Crystallogr Commun. 2019; 75(Pt 1): 21-25. doi.org/ 10.1107/S2056989018017267.
22. Smith M. Wilcox KS. White HS. Discovery of antiepileptic drugs. Neurotherapeutics. 2007; 4(1): 12-7. doi.org/10.1016/j.nurt.2006.11.009.
23. Loscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure. 2011; 20(5): 359-68. doi.org/10.1016/j.seizure.2011.01.003
24. Shubhika J. Bharti Ch. Vybhava K. Isha Kh. Evaluation of Antiepileptic activity of Mosapride in Albino wistar rats. Research Journal of Pharmacy and Technology. 2021; 14(12): 6364-8. DOI: 10.52711/0974-360X.2021.01100.
25. Litchfield JT. Wilcoxon F. A simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 1949; 96, 99–113.
26. Góra M. Czopek A. Rapacz A. Dziubina A. Głuch-Lutwin M. Mordyl B. Obniska J. Synthesis, Anticonvulsant and Antinociceptive Activity of New Hybrid Compounds: Derivatives of 3-(3-Methylthiophen-2-yl)-pyrrolidine-2,5-dione. International Journal of Molecular Sciences. 2020; 21(16): 5750. doi.org/10.3390/ijms21165750.
27. Yogesh RJ. Prabodh VS. Pramod PP. Effect of Nimodipine alone and in combination with Gabapentin against Pentylenetetrazole induced Seizures in Mice. Asian J. Pharm. Res. 2018; 8(4): 215-20. DOI: 10.5958/2231-5691.2018.00036.9.
28. Song M. Zhao W. Zhu Y. LiuW. Deng X. Huang Y. Design, Synthesis, and Evaluation of Anticonvulsant Activities of New Triazolopyrimidine Derivatives. Front. Chem. 2022; 10: 925281. doi.org/10.3389/fchem.2022.925281.
29. Ratna B. Krishna B. Bhavani K. Investigation on the effect of the Drug Levetiracetam combined with Clobazam on MES Model of Epilepsy. Research J. Pharm. and Tech. 2020; 13(6): 2792-96.DOI: 10.5958/0974-360X.2020.00496.5.
30. Gasparyan H. Buloyan S. Pogosyan A. Arshakyan L. Harutyunyan L. Paronikyan R. Nazaryan I. Dashyan Sh. Paronikyan E.G. Pathomorphological investigation of neuroprotective activity of new derivatives of fused pyrazolyl-thienopyridines in Corazol-induced seizures. Clin. exp. morphology. 2021; 10(4): 53–62. doi.org/10.31088/CEM2021.10.4.53-62.
31. Watson C. Kirkcaldie M. Paxinos G. Nissl stain. Techniques for studying the brain. In The Brain, Academic Press, 2010; (11): 153-65. doi.org/10.1016/B978-0-12-373889-9.50011-5.
32. Subamalani S. Sasikumar A. Vijayaragavan R. Senthilkumar S. Madhan KS. Makesh Raj LS. Kannan I. Effect of Acorus calamus Linn on histomorphometric changes in the CA1 and CA3 regions of Hippocampus in Wistar Albino rats. Research J. Pharm. and Tech. 2019; 12(7): 3531-3536. DOI: 10.5958/0974-360X.2019.00601.2.
33. Rajic Z. Zorc B. Raic-Malic S. Ester K. Kralj M. Pavelic K. Balzarini J. De Clercq E, Mintas M. Hydantoin derivatives of L- and D-amino acids: synthesis and evaluation of their antiviral and antitumoral activity. Molecules. 2006; 11(11): 837-48. doi.org/10.3390/11110837.
34. Kleemann A. Engel J. Kutscher B. et al. Pharmaceutical Substances, Synthesis, Patents, Applications. Thieme: Stuttgart, 2009; 5th ed doi.org/10.1055/b-003-108611.
35. Fiallo MM. Kozlowski H. Garnier-Suillerot A. Mitomycin antitumor compounds. Part 1. CD studies on their molecular structure. Eur J Pharm Sci. 2001; 12(4): 487-94. doi.org/10.1016/s0928-0987(00)00200-1.
36. Paronikyan R. Harutyunyan A. Grigoryan A. Barkhudaryants I. Syntez and neurotropic action of derivative hydantoin and dilantin. Bulletin of the Medical College After Mehrabyan, 2022; 13: 69-80. doi.org/10.53821/1829040x-2022.13-69.
37. Paronikyan R. Arshakyan L. Gasparyan H. Buloyan S. Pogosyan A. Morphological and histochemical properties of hydantoin and dilantin derivatives. Bulletin of the Medical College After Mehrabyan, 2022; 13: 81-8. doi.org/10.53821/1829040X-2022.13-81.
38. Bialer M. White HS. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov. 2010; 9(1): 68-82. doi.org/10.1038/nrd2997.
39. Giardina WJ. Gasior M. Acute seizure tests in epilepsy research: electroshock- and chemical-induced convulsions in the mouse. Curr Protoc Pharmacol. 2009; 5(5): 22. doi.org/10.1002/0471141755.ph0522s45.
40. Steward O. Torre ER. Tomasulo R. Lothman E. Seizures and the regulation of astroglial gene expression. Epilepsy Res. 1992; 7: 197-209.
41. Altmann A. Ryten M. Di Nunzio M. Ravizza T. Tolomeo D. et al. A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies. Neuropathol Appl Neurobiol. 2022; 48(1): e12758. doi.org/10.1111/nan.12758.
42. de Lanerolle NC. Lee TS. Spencer DD. Histopathology of Human Epilepsy. In: Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK98141/.
43. Shasmitha R. Saravana Kumar S. Dose dependent effect of Bacopa monnieri on Stress included Neural Degeneration in CA-1 and CA-3 Hippocampus Region of rat. Research J. Pharm. and Tech. 2019; 12(5): 2353-55. DOI: 10.5958/0974-360X.2019.00393.7.
44. Salah RS. Ahmed HH. Abd-Allah SH., Hassan RE. Khalil WKB. Abd-Rabou AA. Sabry GM. The Anti-epileptic Efficiency of Mesenchymal Stem Cells Against Pilocarpine Model of Acute Epilepsy. Research J. Pharm. and Tech. 2021; 14(3): 1255-1266.DOI: 10.5958/0974-360X.2021.00223.7.
45. Bernasconi N. Bernasconi A. Caramanos Z. Antel SB. Andermann F, Arnold DL. Mesial temporal damage in temporal lobe epilepsy: a volumetric MRI study of the hippocampus, amygdala and parahippocampal region. Brain. 2003; 126(Pt 2): 462-9. doi.org/10.1093/brain/awg034.
46. Vismer MS. Forcelli PA. Skopin MD. Gale K. Koubeissi MZ. The piriform, perirhinal, and entorhinal cortex in seizure generation. Front Neural Circuits. 2015; 9: 27. doi.org/10.3389/fncir.2015.00027.
47. Du F. Whetsell WO Jr. Abou-Khalil B. Blumenkopf B. Lothman EW. Schwarcz R. Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy. Epilepsy Res. 1993; 16(3): 223-33. doi.org/10.1016/0920-1211(93)90083-j.
48. Yu C. Deng XJ. Xu D. Microglia in epilepsy. Neurobiol Dis. 2023; 185: 106249. doi.org/10.1016/j.nbd.2023.106249.
49. Kinoshita S. Koyama R. Pro- and anti-epileptic roles of microglia. Neural Regen Res. 2021; 16(7): 1369-71. doi.org/10.4103/1673-5374.300976.
50. Luo C. Ikegaya Y. Koyama R. Microglia and neurogenesis in the epileptic dentate gyrus. Neurogenesis (Austin). 2016; 3(1): e1235525. doi.org/10.1080/23262133.2016.1235525.
51. Zhou QG. Nemes AD. Lee D. Ro EJ. Zhang J. Nowacki AS. Dymecki SM. Najm IM. Suh H. Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits. J Clin Invest. 2019; 129(1): 310-23. doi.org/10.1172/JCI95731.
52. Prentice H. Modi JP. Wu JY. Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases. Oxid Med Cell Longev. 2015; 2015: 964518. doi.org/10.1155/2015/964518.
53. Husna M. Handono K., Sujuti H. et al. Long-term Rapamycin Treatment Inhibit AKT Activity and Lower Intracellular Calcium Expression in Organotypic Hippocampal Slice Cultures Model of Epilepsy. Research Journal of Pharmacy and Technology. 2024; 17(3): 1232-9. DOI: 10.52711/0974-360X.2024.00192.
54. Yu C. Deng XJ. Xu D. Microglia in epilepsy. Neurobiol Dis. 2023; 185: 106249. doi.org/10.1016/j.nbd.2023.106249.