Anticonvulsive potential of cardiac glycosides under conditions of pentilentetrazole-induced seizures in mice: comparative study
Aim. The research provides a comparative analysis of the possible anticonvulsant action of different cardiac glycosides, namely: digoxin, lanatoside C, strophanthin G and corglycone. In addition, it detrmines the leading medication among the abovementioned ones by dose-dependence of its anticonvulsant action.
Material and Methods. The research was performed on 66 random-bred albino male mice. The anticonvulsant effect of cardiac glycosides was studied in a baseline model of pentylenetetrazole-induced seizures. The first series of experiment evaluated the effect of cardiac glycosides on the course of model seizures in comparable doses of approximately 1/10 LD50 for the corresponding drug: digoxin, lanatoside C and strophanthin G - at a dose of 0.8 mg/kg; corglycone - at a dose of 1 mg/kg. The second series of experiments used the drug-leader, which was digoxin, in a wide dose range from 0.2 to 1.6 mg/kg. Digoxin, strophanthin G and corglycone were administered subcutaneously for 15 minutes, lanatoside C - intragastrically for 30 minutes before the induction of experimental seizures. Convulsive agent - pentylenetetrazole in the form of an aqueous solution was administered to animals subcutaneously at a dose of 80 mg/kg.
Results and Discussion. Digoxin at a dose of 0.8 mg/kg under conditions of pentylenetetrazole-induced seizures shows a pronounced anticonvulsant activity: it is the only one among the studied cardiac glycosides that probably reduces lethality. In addition, digoxin prolongs the latency period of the first attacks, and reduces the number of clonic-tonic paroxysms in 1 mouse. Moderate anticonvulsant properties of lanatoside C were found both by a statistically significant decrease in the number of clonic-tonic seizures in 1 mouse, and by a significant reduction in the duration of the convulsive period. Although strophanthin G is unlikely to affect lethality, it moderately reduces the severity of pentylenetetrazole-induced seizures in mice, as evidenced by a statistically significant prolongation of the latency period of the first seizures, as well as a decrease in the number of clonic-tonic seizures in 1 mouse and the duration of seizures. Prophylactic administration of corglycone only prolongs the latency period of seizures and significantly reduces the number of clonic-tonic seizures in 1 mouse. The results of the dose-dependence study of digoxin anticonvulsant action show a clear anticonvulsant potential of this cardiac glycoside in a wide range of doses - from 0.2 to 1.6 mg/kg - with a maximum effect at a dose of 0.8 mg/kg.
Conclusions. It was found that cardiac glycosides have a different severity of anticonvulsant effect: the most powerful anticonvulsant effect is due to digoxin, lanatoside C and strophanthin G have moderate properties, and the least pronounced effect is characteristic to corglycone. In addition, it was determined that digoxin exhibits anticonvulsant properties in a wide range of doses, and has the most pronounced anticonvulsant effect at a dose of 0.8 mg/kg. The obtained results substantiate the expediency of further in-depth study of digoxin as an anticonvulsant medicine.
Abramovici S, Bagi? A: Epidemiology of epilepsy. Neuroepidemiology 2016, 138, 159-171.
Borowicz K, Banach M: Antiarrhythmic drugs and epilepsy. Pharmacological Reports 2014, 66 (4), 545-551.
Botelho AFM, Pierezan F, Soto-Blanco B, Melo MM: A review of cardiac glycosides: Structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential. Toxicon 2019, 158, 63-68.
De Lores Arnaiz GR, Ordieres MG: Brain Na+, K+-ATPase Activity In Aging and Disease. International Journal of Biomedical Science 2014, 10 (2), 85-102.
Elgarhi R, Shehata MM, Abdelsameea AA, Salem AE: Effects of Diclofenac Versus Meloxicam in Pentylenetetrazol-Kindled Mice. Neurochem Res 2020, 45 (8), 1913-1919.
Erdogan MA, Yusuf D, Christy J, Solmaz V, Erdogan A, Taskiran E, Erbas O: Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy. BMC Neurol. 2018, 18 (1), 81.
Hock FJ: Drug Discovery and Evaluation: Pharmacological Assays. Ed.: Hock FJ. Springer International Publishing 2016, 1487-1488.
Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V: The epidemiology of drug-resistant epilepsy: A systematic review and meta-analysis. Epilepsia 2018, 59 (12), 2179-2193.
Loscher W: The holy grail of epilepsy prevention: Preclinical approaches to antiepileptogenic treatments. Neuropharmacology 2020, 167, 107605.
Patocka J, Nepovimova E, Wu W, Kuca K: Digoxin: Pharmacology and toxicology - A review. Environ Toxicol Pharmacol 2020, 79, 103400.
Quintana-Pajaro LJ, Ramos-Villegas Y, Cortecero-Sabalza E, Joaquim AF, Agrawal A, Narvaez-Rojas AR, Moscote-Salazar LR: The Effect of Statins in Epilepsy: A Systematic Review. J Neurosci Rural Pract 2018, 9 (4), 478-486.
Santos MS, Goncalves PP, Carvalho AP: Effect of ouabain on the gamma-[3H]aminobutyric acid uptake and release in the absence of Ca(+)+ and K(+)-depolarization. J Pharmacol Exp Ther 1990, 253 (2), 620-627.
Scicchitano F, Constanti A, Citraro R, De Sarro G, Russo E: Statins and epilepsy: preclinical studies, clinical trials and statin-anticonvulsant drug interactions. Curr Drug Targets 2015, 16 (7), 747-56.
Shtrygol' S., Shtrygol' D. Digoxin as an antiepileptic in children (clinical and experimental study). Ukrainian Medical Almanac 2010, 13: 164. Russian
Stoletov Y.V., Kutsenko T.A., Ulanov V.A., Belik G.V. Experience and prospects of using medicinal plants for the treatment of coronary heart disease. In: Scientific discoveries: projects, strategies and development (volume 2). Edinburg; 2019. pp. 49-55. Russian
Suemaru K, Yoshikawa M, Tanaka A, Araki H, Aso H, Watanabe M: Anticonvulsant effects of acetaminophen in mice: Comparison with the effects of nonsteroidal anti-inflammatory drugs. Epilepsy Res 2018, 140, 22-28.
Tsyvunin V, Shtrygol' S, Shtrygol' D: Digoxin enhances the effect of antiepileptic drugs with different mechanism of action in the pentylenetetrazole-induced seizures in mice. Epilepsy Res 2020, 167, 106465.
Waller D, Sampson A: Heart failure. In: Medical Pharmacology and Therapeutics. Eds.: Waller D, Sampson A, Elsevier 2017, 5th ed., 131-142.
Wei D, Peng JJ, Gao H, Li H, Li D, Tan Y, Zhang T: Digoxin downregulates NDRG1 and VEGF through the inhibition of HIF-1a under hypoxic conditions in human lung adenocarcinoma A549 cells. Int J Mol Sci 2013, 14 (4), 7273-7285.
Yimer EM, Surur A, Wondafrash DZ, Gebre AK: The Effect of Metformin in Experimentally Induced Animal Models of Epileptic Seizure. Behav Neurol 2019, 4, 6234758.
Zadvornov А.А., Golomidov А.V., Grigoriev E.V. Clinical pathophysiology of cerebral edema (part 2). Messenger of Anesthesiology and Resuscitation 2017, 14 (4): 52-60. Russian
Zeiler FA, Zeiler KJ, Kazina CJ, Teitelbaum J, Gillman LM, West M: Lidocaine for status epilepticus in adults. Seizure 2015, 31, 41-48.
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