Digoxin at sub-cardiotonic dose modulates the anticonvulsive potential of valproate, levetiracetam and topiramate in experimental primary generalized seizures

Abstract

The prevalence of epilepsy in the world population together with a high percentage of patients resistant to existing antiepileptic drugs (AEDs) stimulates the constant search for new approaches to the treatment of the disease. Previously a significant anticonvulsant potential of cardiac glycoside digoxin has been verified by enhancing a weak activity of AEDs in low doses under screening models of seizures induced by pentylenetetrazole and maximal electroshock. The aim of the present study is to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant activity of valproate, levetiracetam, and topiramate in models of primary generalized seizures with different neurochemical mechanisms. A total of 264 random-bred male albino mice have been used. AEDs were administered 30 min before seizure induction once intragastrically at conditionally effective (ED50) and sub-effective (½ ED50) doses: sodium valproate and topiramate – at doses of 300 and 150 mg/kg; levetiracetam – at doses of 100 and 50 mg/kg. Digoxin was administered once subcutaneously at a dose of 0.8 mg/kg body weight (1/10 LD50) 10–15 min before seizure induction. Picrotoxin (aqueous solution 2.5 mg/kg, subcutaneously), thiosemicarbazide (aqueous solution 25 mg/kg, intraperitoneally), strychnine (aqueous solution 1.2 mg/kg, subcutaneously), camphor (oil solution 1000 mg/kg, intraperitoneally) have been used as convulsive agents for seizure induction. It was found that under the conditions of primary generalized seizures induced by picrotoxin, thiosemicarbazide, strychnine, and camphor, digoxin not only shows its own strong anticonvulsant activity but also significantly enhances the anticonvulsant potential of classical AEDs sodium valproate, levetiracetam, and topiramate. The obtained results substantiate the expediency of further in-depth study of digoxin as an anticonvulsant drug, in particular, the in-depth study of neurochemical mechanisms of its action.

Digoxin and sodium valproate, but not celecoxib, render a pronounced effect on the cerebral cyclooxygenase pathway and neuron-specific enolase under the pentylenetetrazole-induced kindling in mice

“…In previous studies, we found the presence of a pronounced anticonvulsant effect of digoxin per se, as well as its potentiating effect on classical commonly used antiepileptic drugs (AEDs) in acute primarly generalized models of seizure, induced by pentylenetetrazole (PTZ), picrotoxin, thiosemicarbazide, strychnine, camphor and maximal electroshock in mice (Tsyvunin et al 2020(Tsyvunin et al -2022.…”

SGLT-2 inhibitors as potential anticonvulsants: empagliflozin, but not dapagliflozin, renders a pronounced effect and potentiates the sodium valproate activity in pentylenetetrazole-induced seizures

“…The use of non-antiepileptic medicines as adjuvant agents, which have anticonvulsant properties and enhance the effects of classical AEDs, is gaining more comprehensive application. Such medicines include, in particular, non-steroidal anti-inflammatory medicines, sodium channel blockers (in particular, lidocaine), slow calcium channel blockers, β-blockers, the If-channel blocker ivabradine, the competitive xanthine oxidase inhibitor allopurinol, statins, selective phosphodiesterase-5 inhibitors (sildenafil, tadalafil), the cardiac glycoside digoxin [5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”