Assessment of the Combined Treatment with Umbelliferone and Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Abstract

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.

Isobolographic Analysis of Interaction for Three-Drug Combination of Carbamazepine, Phenobarbital and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

“…in a volume of 5 ml/kg body weight. Fresh drug solutions were administered as follows: CBZ at 30 min, PB and TPM at 60 min, prior to maximal electroconvulsions as reported earlier [10,11] .…”

C-11, a New Antiepileptic Drug Candidate: Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model

“…The pretreatment times before testing of the antiepileptic drugs were based on information about their biological activity from the literature [ 20 ], and our previous experiments [ 12 , 13 , 14 ]. The pretreatment time (30 min) before testing C-11 was established in our previous study as the time to peak of maximum anticonvulsant activity of C-11 [ 15 ].…”

“…Due to this, there is an urgent need to develop a new class of active compounds with anticonvulsant and neuroprotective properties while being non-toxic. Over the past few years, our team has focused on the search for new substances, both natural and synthetic, that have such properties, and may have a magnifying effect on commercially used AEDs, increasing their anticonvulsant activity [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

Natural Medicines for the Treatment of Epilepsy: Bioactive Components, Pharmacology and Mechanism

“…Moreover, α-asarum plays a protective role in cases of treatment-resistant epilepsy that induced neuronal cell membrane damage through the inhibition of the laminin-1 expression (Huang et al, 2013). Other compounds have been found to exert antiepileptic effects in pharmacological studies, such as umbelliferone (UMB; Zagaja et al, 2015), erysothrine (Rosa et al, 2012), resveratrol, and catechin (Ahmad et al, 2020). In addition, the anticonvulsant and epileptic effects of some protein components have also been studied.…”

“…Systemic intraperitoneal (ip) administration of UMB at a dosage of 150 mg/kg could significantly elevate the threshold for EMS in mice. The selective potentiation of the anticonvulsant potency of phenobarbital and valproate by UMB and the lack of any pharmacokinetic interactions between the drugs make the combinations of UMB with phenobarbital or valproate worthy of consideration for refractory epileptic patients (Zagaja et al, 2015).…”