Ukr.Biochem.J. 2021; Volume 93, Issue 2, Mar-Apr, pp. 53-60

doi: https://doi.org/10.15407/ubj93.02.053

Oxidative stress suppression contributes to antiseizure action of axitinib and rapamycin in pentylenetetrazol-induced kindling

18.05.2021   Uncategorized   No comments

O. B. Poshyvak1*, O. R. Pinyazhko1,2, L. S. Godlevsky3

1Pharmacology Department, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine;
2Department of Civilization Diseases and Regenerative Medicine, WSIiZ, Rzeszow, Poland;
3Department of Biophysics, Informatics and Medical Devices, Odesa National Medical University, Odesa, Ukraine;
*e-mail: olesya.poshyvak@gmail.com

Received: 29 January 2021; Accepted: 23 April 2021

Rapamycin and axitinib block different kinases in signaling pathways such as PI3K-Akt-mTOR and BDNF-TrkB, respectively. Both have antiseizure and antioxidative actions, which justify studying the combined effects of these drugs upon seizures and oxidative stress in the chronic model of epilepsy. The investigation aimed to look for the combined effect of rapamycin and axitinib upon pentylenetetrazol (PTZ)-kindled seizures and oxidative stress. Experiments were performed on 300 two- to four-month-old Wistar male rats, which had been kindled daily with PTZ (35.0 mg/kg, i.p.). Malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, and glutathione (GSH) level were determined in brain tissues of kindled rats before and after the treatment. The analysis of antiseizure and antioxidative actions was performed using ED50 of rapamycin and axitinib, with their combined administration using graded dosages of ED50 of each drug. The median effective dose (ED50) for rapamycin and axitinib was 0.93 and 4.97 mg/kg, respectively. ED50 of rapamycin when combined with axitinib (2.0 mg/kg) was 0.60 mg/kg, which was reduced by 35.6% when compared with the ED50 administered alone (P < 0.05). The MDA level increased from 152.9±24.8 to 388.3±49.2 nmol/mg of protein (P < 0.05), while SOD activity reduced from 11.14±2.33 to 3.54±1.08 IU/mg of protein (P < 0.05) in brain tissues of the kindled rats. Combined treatment with rapamycin (0.56 mg/kg, i.p.) and axitinib (2.0 mg/kg, i.p.) resulted in a significant rise in SOD activity (11.09±1.86 IU/mg) and GSH level (7.32±1.34 µg/mg) when compared with the kindled rats (P < 0.05). Combined axitinib and rapamycin therapy have an antiepileptic and antioxidative effect on PTZ-kindled seizures.

Keywords: , , , ,

References:

  1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, Engel  JJr, Forsgren L, French JA, Glynn M, DC Hesdorffer, Lee BI, Mathern GW, Moshé SL, Perucca E, Scheffer IE, Tomson T, Watanabe M, Wiebe S. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-482.  PubMed, CrossRef
  2. Chubach VS, Muratova TN, Myronenko SI, Godlevsky LS. Antiepileptic effects of axitinib on pentylenetetrazol- induced kindling in rats. Epilepsia. 2015; 56 (Suppl 1): 0142.
  3. Liu J, Schenker M, Ghiasvand S, Berdichevsky Y. Kinase inhibitors with antiepileptic properties identified with a novel in vitro screening platform. Int J Mol Sci. 2019;20(10):2502.  PubMed, PubMedCentral, CrossRef
  4. Zeng LH, Rensing NR, Wong M.  The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci. 2009;29(21):6964-6972. PubMed, PubMedCentral, CrossRef
  5. Buckmaster PS, Ingram EA, Wen X. Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. J Neurosci. 2009;29(25):8259-8269. PubMed, PubMedCentral, CrossRef
  6. Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, Cao Z, Gruenthal M, Huang Y. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis. 2010;40(1):193-199. PubMed, PubMedCentral, CrossRef
  7. van Vliet EA, Forte G, Holtman L, den Burger JCG, Sinjewel A, de Vries HE, Aronica E, Gorter JA. Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia. 2012;53(7):1254-1263. PubMed, CrossRef
  8. Wang F, Chen F, Wang G, Wei S, Fang F, Kang D, Lin Y. Rapamycin provides anti-epileptogenic effect in a rat model of post-traumatic epilepsy via deactivation of mTOR signaling pathway. Exp Ther Med. 2018;15(6):4763-4770. PubMed, PubMedCentral, CrossRef
  9. Godlevsky LS, Shandra AA, Oleinik AA, Vastyanov RS, Kostyushov VV, Timchishin OL. TNF-alpha in cerebral cortex and cerebellum is affected by amygdalar kindling but not by stimulation of cerebellum. Pol J Pharmacol. 2002;54(6):655-660. PubMed
  10. Jesus M, Martins APJ, Gallardo E, Silvestre S. Diosgenin: recent highlights on pharmacology and analytical methodology. J Anal Methods Chem. 2016;2016:4156293. PubMed, PubMedCentral, CrossRef
  11. Zhu X, Dong J, Shen K, Bai Y, Zhang Y, Lv X, Chao J, Yao H. NMDA receptor NR2B subunits contribute to PTZ-kindling-induced hippocampal astrocytosis and oxidative stress. Brain Res Bull. 2015;114:70-78.  PubMed, CrossRef
  12. Geronzi U, Lotti F, Grosso S. Oxidative stress in epilepsy. Expert Rev Neurother. 2018;18(5):427-434. PubMed, CrossRef
  13. Shandra AA, Mazarati AM, Godlevsky LS, Vastyanov RS. Chemical kindling: implications for antiepileptic drugs – sensitive and resistant epilepsy models. Epilepsia. 1996;37(3):269-274. PubMed, CrossRef
  14. Jiang J, Jiang J, Zuo Y, Gu Z. Rapamycin protects the mitochondria against oxidative stress and apoptosis in a rat model of Parkinson’s disease. Int J Mol Med. 2013;31(4):825-832. PubMed, CrossRef
  15. Singh AK, Singh S, Garg G, Rizvi SI. Rapamycin alleviates oxidative stress-induced damage in rat erythrocytes. Biochem Cell Biol. 2016;94(5):471-479. PubMed, CrossRef
  16. Mihajlovic M, Ivkovic B, Jancic-Stojanovic B, Zeljkovic A, Spasojevic-Kalimanovska V, Kotur-Stevuljevic J, Vujanovic D. Modulation of oxidative stress/antioxidative defence in human serum treated by four different tyrosine kinase inhibitors. Anticancer Drugs. 2020;31(9):942-949. PubMed, CrossRef
  17. Godlevsky LS, Muratova TN, Kresyun NV, van Luijtelaar G, Coenen AML. Anxiolytic and antidepressive effects of electric stimulation of the paleocerebellar cortex in pentylenetetrazol kindled rats. Acta Neurobiol Exp (Wars). 2014;74(4):456-464. PubMed
  18. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-358. PubMed, CrossRef
  19. Kono Y.  Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys. 1978;186(1):189-195. PubMed, CrossRef
  20. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. 1968;25(1):192-205. PubMed, CrossRef
  21. Lorwy OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-275. PubMed, CrossRef
  22. Ghasemnejad-Berenji M, Ghazi-Khansari M, Pashapour S, Jafari A, Yazdani I, Ghasemnejad-Berenji H, Saeedi Saravi SS, Sadeghpour S, Nobakht M, Abdollahi A, Mohajer Ansari  J, Dehpour AR. Synergistic effect of rapamycin and metformin against germ cell apoptosis and oxidative stress after testicular torsion/detorsion-induced ischemia/reperfusion in rats. Biomed Pharmacother. 2018;105:645-651. PubMed, CrossRef
  23. Suyani E, Derici UB, Sahin T, Ofluoglu E, Pasaoglu H, Erdem O, Barit G, Reis KA, Erten Y, Arinsoy T, Sindel S. Effects of everolimus on cytokines, oxidative stress, and renal histology in ischemia-reperfusion injury of the kidney. Ren Fail. 2009;31(8):698-703. PubMed, CrossRef
  24. Rosing K, Fobker M, Kannenberg F, Gunia S, Dell’Aquila AM, Kwiecien R, Stypmann J, Nofer JR. Everolimus therapy is associated with reduced lipoprotein-associated phospholipase A2 (Lp-Pla2) activity and oxidative stress in heart transplant recipients. Atherosclerosis. 2013;230(1):164-170.
    PubMed, CrossRef
  25. Teppo HR, Soini Y, Karihtala P. Reactive Oxygen Species-Mediated Mechanisms of Action of Targeted Cancer Therapy. Oxid Med Cell Longev. 2017;2017:1485283. PubMed, PubMedCentral, CrossRef
  26. Fahnestock M, Nicolini C. Bridging the gap between genes and behavior: Brain-derived neurotrophic factor and the mTOR pathway in idiopathic autism. Autism Open Access. 2015; 5:2. CrossRef
  27. Moya-Alvarado G, Bronfman FC. BDNF/TrkB mediates long-distance dendritic growth by activating CREB/PI3K-mTOR-dependent translation in neuronal cell bodies. bioRxiv. 2020.08.22.262923.  CrossRef
Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.