Background/Aims: The aim of this study was to determine the effects of umbelliferone (7-hydroxycoumarin; UMB) on the anticonvulsant potency of four classical antiepileptic drugs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) and valproate (VPA)) in the mouse maximal electroshock-induced seizure (MES) model. Results: UMB administered systemically intraperitoneally (ip) in a dose of 150 mg/kg significantly elevated the threshold for maximal electroconvulsions (p < 0.05) in mice. Moreover, UMB (150 mg/kg) co-administered with PB and VPA significantly enhanced the anticonvulsant potency of these drugs by reducing their median effective doses (ED50 values) from 35.39 to 21.78 mg/kg (p < 0.01) for PB, and from 281.4 to 215.5 mg/kg (p < 0.01) for VPA. In contrast, UMB (150 mg/kg, ip) had no significant effect on the antiseizure activity of CBZ and PHT in the mouse MES model. Neither total brain PB, nor total brain VPA concentrations were altered after ip administration of UMB, indicating a pharmacodynamic nature of interactions between the tested drugs. Conclusions: The selective potentiation of the anticonvulsant potency of PB and VPA by UMB, and lack of any pharmacokinetic interactions between drugs, make the combinations of UMB with PB or VPA worthy of consideration for epileptic patients who are refractory to standard antiepileptic treatment.

Keywords:
Umbelliferone (7-hydroxycoumarin), Mouse maximal electroshock-induced seizure model, High-performance counter-current chromatography
1.
Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 2000;342:314-319.
2.
Kwan P, Brodie MJ: Epilepsy after the first drug fails: substitution or add-on? Seizure 2000;9:464-468.
3.
Malawska B: New anticonvulsant agents. Curr Top Med Chem 2005;5:69-85.
4.
Vasconcelos JF, Teixeira MM, Barbosa-Filho JM, Agra MF, Nunes XP, Giulietti AM, Ribeiro-Dos-Santos R, Soares MB: Effects of umbelliferone in a murine model of allergic airway inflammation. Eur J Pharmacol 2009;609:126-131.
5.
Ramesh B, Pugalendi KV: Antihyperglycemic effect of umbelliferone in streptozotocin-diabetic rats. J Med Food 2006;9:562-566.
6.
Ramesh B, Pugalendi KV: Influence of umbelliferone on glycoprotein components in diabetic rats. Toxicol Mech Methods 2007;17:153-159.
7.
Ramesh B, Pugalendi KV: Antihyperlipidemic and antidiabetic effects of umbelliferone in streptozotocin diabetic rats. Yale J Biol Med 2005;78:189-196.
8.
Ramesh B, Pugalendi KV: Antioxidant role of Umbelliferone in STZ-diabetic rats. Life Sci 2006;79:306-310.
9.
Skalicka-Woźniak K, Głowniak K: Pressurized liquid extraction of coumarins from fruits of Heracleum leskowii with application of solvents with different polarity under increasing temperature. Molecules 2012;17:4133-4141.
10.
Barros TA, de Freitas LA, Filho JM, Nunes XP, Giulietti AM, de Souza GE, dos Santos RR, Soares MB, Villarreal CF: Antinociceptive and anti-inflammatory properties of 7-hydroxycoumarin in experimental animal models: potential therapeutic for the control of inflammatory chronic pain. J Pharm Pharmacol 2010;62:205-213.
11.
de Lima FO, Nonato FR, Couto RD, Barbosa Filho JM, Nunes XP, Ribeiro dos Santos R, Soares MB, Villarreal CF: Mechanisms involved in the antinociceptive effects of 7-hydroxycoumarin. J Nat Prod 2011;74:596-602.
12.
Wu L, Wang X, Xu W, Farzaneh F, Xu R: The structure and pharmacological functions of coumarins and their derivatives. Curr Med Chem 2009;16:4236-4260.
13.
Toyama DO, Marangoni S, Diz-Filho EB, Oliveira SC, Toyama MH: Effect of umbelliferone (7-hydroxycoumarin, 7-HOC) on the enzymatic, edematogenic and necrotic activities of secretory phospholipase A2 (sPLA2) isolated from Crotalus durissus collilineatus venom. Toxicon 2009;53:417-426.
14.
Lake BG: Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessment. Food Chem Toxicol 1999;37:423-453.
15.
Kanimozhi G, Prasad NR, Ramachandran S, Pugalendi KV: Umbelliferone modulates gamma-radiation induced reactive oxygen species generation and subsequent oxidative damage in human blood lymphocytes. Eur J Pharmacol 2011;672:20-29.
16.
Li D, Ellis EM: Inducible protection of human astrocytoma 1321N1 cells against hydrogen peroxide and aldehyde toxicity by 7-hydroxycoumarin is associated with the upregulation of aldo-keto reductases. Neurotoxicology 2012;33:1368-1374.
17.
Kurokawa M, Watanabe W, Shimizu T, Sawamura R, Shiraki K: Modulation of cytokine production by 7-hydroxycoumarin in vitro and its efficacy against influenza infection in mice. Antiviral Res 2010;85:373-380.
18.
Zhao D, Islam MN, Ahn BR, Jung HA, Kim BW, Choi JS: In vitro antioxidant and anti-inflammatory activities of Angelica decursiva. Arch Pharm Res 2012;35:179-192.
19.
Islam MN, Choi RJ, Jin SE, Kim YS, Ahn BR, Zhao D, Jung HA, Choi JS: Mechanism of anti-inflammatory activity of umbelliferone 6-carboxylic acid isolated from Angelica decursiva. J Ethnopharmacol 2012;144:175-181.
20.
Timonen JM, Nieminen RM, Sareila O, Goulas A, Moilanen LJ, Haukka M, Vainiotalo P, Moilanen E, Aulaskari PH: Synthesis and anti-inflammatory effects of a series of novel 7-hydroxycoumarin derivatives. Eur J Med Chem 2011;46:3845-3850.
21.
Stefanova T, Nikolova N, Neychev H, Zlabinger G: Phagocytosis and killing of salmonella by 7-hydroxycoumarin activated macrophages. Immunol Invest 2012;41:199-213.
22.
Luszczki JJ, Glowniak K, Czuczwar SJ: Time-course and dose-response relationships of imperatorin in the mouse maximal electroshock seizure threshold model. Neurosci Res 2007;59:18-22.
23.
Luszczki JJ, Glowniak K, Czuczwar SJ: Imperatorin enhances the protective activity of conventional antiepileptic drugs against maximal electroshock-induced seizures in mice. Eur J Pharmacol 2007;574:133-139.
24.
Luszczki JJ, Wojda E, Raszewski G, Głowniak K, Czuczwar SJ: Influence of imperatorin on the anticonvulsant activity and acute adverse-effect profile of lamotrigine in maximal electroshock-induced seizures and chimney test in mice. Pharmacol Rep 2008;60:566-573.
25.
Łuszczki JJ, Andres-Mach M, Gleńsk M, Skalicka-Woźniak K: Anticonvulsant effects of four linear furanocoumarins, bergapten, imperatorin, oxypeucedanin, and xanthotoxin, in the mouse maximal electroshock-induced seizure model: a comparative study. Pharmacol Rep 2010;62:1231-1236.
26.
Zagaja M, Pyrka D, Skalicka-Wozniak K, Glowniak K, Florek-Luszczki M, Glensk M, Luszczki JJ: Effect of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of classical antiepileptic drugs against maximal electroshock-induced seizures in mice. Fitoterapia 2015;105:1-6.
27.
Luszczki JJ, Andres-Mach M, Cisowski W, Mazol I, Glowniak K, Czuczwar SJ: Osthole suppresses seizures in the mouse maximal electroshock seizure model. Eur J Pharmacol 2009;607:107-109.
28.
Löscher W, Fassbender CP, Nolting B: The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res 1991;8:79-94.
29.
Kielbus M, Skalicka-Wozniak K, Grabarska A, Jeleniewicz W, Dmoszynska-Graniczka M, Marston A, Polberg K, Gawda P, Klatka J, Stepulak A: 7-Substituted coumarins inhibit proliferation and migration of laryngeal cancer cells in vitro. Anticancer Res 2013;33:4347-4356.
30.
Luszczki JJ, Ratnaraj N, Patsalos PN, Czuczwar SJ: Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Naunyn Schmiedebergs Arch Pharmacol 2006;373:169-181.
31.
Litchfield JT Jr, Wilcoxon F: A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 1949;96:99-113.
32.
Luszczki JJ, Wojda E, Andres-Mach M, Cisowski W, Glensk M, Glowniak K, Czuczwar SJ: Anticonvulsant and acute neurotoxic effects of imperatorin, osthole and valproate in the maximal electroshock seizure and chimney tests in mice: a comparative study. Epilepsy Res 2009;85:293-299.
33.
Luszczki JJ, Danysz W, Czuczwar SJ: Interactions of MRZ 2/576 with felbamate, lamotrigine, oxcarbazepine and topiramate in the mouse maximal electroshock-induced seizure model. Pharmacology 2008;81:259-265.
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2015
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