The Protection by Vitamin E Against Tramadol-Induced Proconvulsant Effects and Brain Damage in Pentylenetetrazole-Induced Status Epilepticus in Rats


  • Omar M.E. Abdel-Salam Department of Toxicology and Narcotics, National Research Centre, Cairo, Egypt
  • Marawan Abd El Baset Mohamed Sayed Department of Pharmacology, National Research Centre, Cairo, Egypt
  • Enayat A. Omara Department of Pathology, National Research Centre, Cairo, Egypt
  • Amany A. Sleem Department of Pharmacology, National Research Centre, Cairo, Egypt



Tramadol, Vitamin E, Epilepsy, Anticonvulsant, Pentylenetetrazole


We investigated the effect of the opioid analgesic tramadol on the development of epileptic seizures and neuronal injury and the possible modulatory effect of vitamin E (Vit E) in rats with pentylenetetrazole (PTZ)-induced status epilepticus. Rats received repeated intraperitoneal (i.p.) injections of PTZ till the development of status epilepticus and were pretreated once with tramadol (30, 60 or 90 mg/kg), vitamin E (Vit E, 70 mg/kg) or both tramadol (90 mg/kg) and Vit E (70 mg/kg) prior to starting PTZ injections. Seizure scores, the latency time and the PTZ dose for each group required to reach status epilepticus were determined and histopathological examination of the brain tissue was done. Results indicated that tramadol produced both anticonvulsant and proconvulsant effects. The anticonvulsant effects of tramadol were observed for facial twitching (stage 1), convulsive body waves (stage 2), and myoclonic jerks and rearing (stage 3) and turn over onto one side position (stage 4) that were significantly inhibited by tramadol. In contrast, tonic-clonic convulsions (stage 5) were significantly increased by 60 or 90 mg/kg of tramadol as compared to PTZ control group. The mean latency and PTZ threshold dose for status epilepticus were markedly decreased after tramadol. The administration of Vit E exerted beneficial effects in decreasing epilepsy scores and increasing both the latency time and threshold dose of PTZ for reaching status epilepticus. Meanwhile, rats treated with both tramadol and Vit E exhibited significant increase in tonic-clonic convulsions and markedly shortened latency time to reach status epilepticus compared to those treated with only Vit E. In cerebral cortex and hippocampus, PTZ resulted in apoptotic cells, darkly stained degenerated and vacuolated neurons and gliosis. These pathological changes increased after tramadol but were markedly reduced by Vit E treatment. Collectively, these results suggest that: (i) tramadol exerts both anticonvulsant and proconvulsant effects; (ii) tramadol shortened the latency time and decreased the threshold dose of PTZ for evoking status epilepticus; (iii) PTZ-induced seizures and brain damage can be inhibited by Vit E; (iv) tramadol at high doses interferes with the effect of Vit E in inhibiting tonic-clonic convulsions and in reducing brain damage.


Surguchov A, Surgucheva I, Sharma M, Sharma R, Singh V. Pore-forming proteins as mediators of novel epigenetic mechanism of epilepsy. Front Neurol 2017; 8: 3. eCollection 2017.

Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43(13): 879-923.

Leppert W. Tramadol as an analgesic for mild to moderate cancer pain. Pharmacol Rep 2009; 61(6): 978-992.

Whittle SL, Richards BL, Husni E, Buchbinder R. Opioid therapy for treating rheumatoid arthritis pain. The Cochrane Library 2011; 11: CD003113.

Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC. Opioids compared to placebo or other treatments for chronic low-back pain. Cochrane Database Syst Rev 2013; 8: CD004959.

Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B. Influence of tramadol on neurotransmitter systems of the rat brain. Arzneimittelforschung 1996; 46: 1029-36.

Raffa RB. Basic pharmacology relevant to drug abuse assessment: tramadol as example. J Clin Pharm Thers 2008; 33: 101-108.

Volpe DA, Tobin GA, Mellon RD, Katki AG, Parker RJ, Colatsky T et al. Uniform assessment and ranking of Mu receptor binding constants for selected opioid drugs. Regulatory Toxicology and Pharmacology 2011; 59: 385-390.

Sprague JE, Leifheit M, Selken J, Milks MM, Kinder DH, Nichols DE. In vivo microdialysis and conditioned place preference studies in rats are consistent with abuse potential of tramadol. Synapse 2002; 43(2): 118-121.

ElShebiney SA, Abuelfadl DA, Abdel-Salam OME. Neurochemical and histological brain alterations after tramadol administration to rotenone- induced Parkinson's disease in rats. Egypt J Forensic Sci Appli Toxicol 2020; 20(1): 15-32.

Thiels CA, Habermann EB, Hooten WM, Jeffery MM. Chronic use of tramadol after acute pain episode: cohort study. BMJ 2019; 365: 1849.

Sansone RA, Sansone LA. Tramadol: seizures, serotonin syndrome, and coadministered antidepressants. Psychiatry (Edgmont) 2009; 6: 17-21.

Bekjarovski N, Chaparoska D, Radulovikj-Bekjarovska S. Seizures after use and abuse of tramadol. Prilozi 2012; 33(1): 313-318.

Dasgupta HS. Low-Dose Tramadol Induced Seizure: A Case Report. Clin Case Rep Int 2022; 6: 1314.

Miotto K, Cho AK, Khalil MA, Blanco K, Sasaki JD, Rawson R. Trends in tramadol: pharmacology, metabolism, and misuse. Anesthesia & Analgesia 2017; 124(1): 44-51.

Dhir A. Pentylenetetrazol (PTZ) kindling model of epilepsy. Curr Protoc Neurosci 2012; Chapter 9:Unit 9.37.

Paget GE, Barnes JM. Toxicity testing. In: Laurence DR, Bacharach AL (eds.), Evaluation of Drug Activities: Pharmacometrics. Academic Press, London, UK: 1964: pp 1-135.

Erkeç ÖE, Arihan O. Pentylenetetrazole kindling epilepsy model pentilentetrazol. Epilepsi 2015; 21(1): 6-12

Corda MG, Orlandi M, Giorgi O. Decrease in GABAA receptor function induced by pentylenetetrazol kindling in the rat: role of N-methyl-D-aspartate (NMDA) receptors. Adv Biochem Psychopharmacol 1992; 47: 235-247.

Löscher W, Rogawski MA. Epilepsy. In: Lodge D, Danysz W, Parsons CG (eds.), Ionotropic glutamate receptors as therapeutic targets. FP Graham Publishing Co., Johnson, 2002, pp. 1-42.

Potschka H, Friderichs E, Löscher W. Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy. Br J Pharmacol. 2000; 131: 203-12.

El-Mansoury AM, Ghanem AAA; Zaghloul MH, Shabka OA, Adel M. Patients with tramadol induced seizures presented to Mansoura University emergency hospital. Mansoura J Forensic Med Clin Toxicol 2016; XXIV (2): 49-62.

Jovanović-Cupić V, Martinović Z, Nesić N. Seizures associated with intoxication and abuse of tramadol. Clin Toxicol (Phila) 2006; 44(2): 143-6.

Gasse C, Derby L, Vasilakis-Scaramozza C, Jick H. Incidence of first-time idiopathic seizures in users of tramadol. Pharmacotherapy 2000; 20: 629-34.

Morrow RL, Dormuth CR, Paterson M, Mamdani MM, Gomes T, Juurlink DN. Tramadol and the risk of seizure: nested case control study of US patients with employer-sponsored health benefits. BMJ Open 2019; 9: e026705.

Rowley S, Patel M. Mitochondrial involvement and oxidative stress in temporal lobe epilepsy. Free Radic Biol Med 2013; 62:121-131.

Geronzi U, Lotti F, Grosso S. Oxidative stress in epilepsy. Expert Rev Neurother 2018; 18(5): 427-434.

Abdel-Salam OME, Sleem AA, Sayed MAEBM, Youness ER, Shaffie N. Capsaicin exerts anti-convulsant and neuroprotective effects in pentylenetetrazole-induced seizures. Neurochem Res 2020; 45(5): 1045-1061.

Abdel-Salam OME, Sleem AA, Sayed MAEBM, Youness ER, Shaffie N. Methylene blue protects against pentylenetetrazole-induced seizures, oxidative stress and neuronal injury. Comp Clin Pathol 2020; 29: 341-354.

Abdel-Salam OME, Youness ER, Sayed MAEBM, Sleem AA, Shaffie N. Inhibition of pentylenetetrazole-induced seizures and neuronal injury by brilliant blue g: role of oxidative stress, and brain derived neurotrophic factor. Egypt J Chem 2022; 65(8): 215-225.

Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr 2004; 134: 489-492.

Akbas SH, Yegin A, Ozben T. Effect of pentylenetetrazolinduced epileptic seizure on the antioxidant enzyme activities, glutathione and lipid peroxidation levels in rat erythrocytes and liver tissues. Clin Biochem 2005; 38(11): 1009-1014.

Burton GW. Vitamin E: molecular and biological function. Proceedings of the Nutrition Society 1994; 53: 251-262

Traber MG, Atkinson J. Vitamin E, antioxidant and nothing more. Free Radic Biol Med. 2007; 43(1): 4-15.

Navarro A, Gomez C, Sanchez-Pino MJ, Gonzalez H, Bandez MJ, Boveris AD e al. Vitamin E at high doses improves survival, neurological performance, and brain mitochondrial function in aging male mice. Am J Physiol Regul Integr Comp Physiol 2005; 289: R1392-R1399.

Ulatowski L, Parker R, Warrier G, Sultana R, Butterfield DA, Manor D. Vitamin E is essential for Purkinje neuron integrity. Neuroscience 2014; 260:120-129.

Ekonomou A, Angelatou F. Upregulation of NMDA receptors in hippocampus and cortex in the pentylenetetrazol-induced "kindling" model of epilepsy. Neurochemical Res 2000; 24(12): 1515-22.

Pohle W, Becker A, Grecksch G, Juhre A, Willenberg A. Piracetam prevents pentylenetetrazol kindling-induced neuronal loss and learning deficits. Seizure 1997; 6(6): 467-474.

Abdel-Salam OME, Sleem AA, Youness ER, Omara EA. Identification of biomarkers for the detection of subtle brain injury after cannabis and/or tramadol administration. Egypt J Forensic Sci 2019; 9: 58.

Ghoneim FM, Khalaf HA, Elsamanoudy AZ, Helaly AN. Effect of chronic usage of tramadol on motor cerebral cortex and testicular tissues of adult male albino rats and the effect of its withdrawal: histological, immunohistochemical and biochemical study. Int J Clin Exp Pathol 2014; 7: 7323-7341.

Ragab IK, Mohamed HZE. Histological changes of the adult albino rats entorhinal cortex under the effect of tramadol administration: Histological and morphometric study. Alex J Med 2017; 53 (2): 123-133.




How to Cite

Abdel-Salam, O. M. ., Mohamed Sayed, M. A. E. B. ., A. Omara, E. ., & A. Sleem, A. . (2023). The Protection by Vitamin E Against Tramadol-Induced Proconvulsant Effects and Brain Damage in Pentylenetetrazole-Induced Status Epilepticus in Rats. Journal of Neurology and Epidemiology, 8, 1–10.