in vitro epilepsy model | Acta Medica Marisiensis

In vitro modulation of seizure-like activity with beta-cyclodextrin-complexed rufinamide

Rita-Judit Kiss¹, Zsolt András Nagy², Ádám Szentes², Ágnes Csüdör², Andrea Máthé², Henrietta Makó², Előd Bomher², Ádám József Berki³, Zsolt Gáll⁴, Tibor Szilágyi¹, Károly Orbán-Kis¹

1. Physiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania
2. George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania
3. Department of Neurology, Semmelweis University, Budapest, Hungary
4. Pharmacology and Clinical Pharmacy Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania

DOI: 10.2478/amma-2024-0020

Objective: The global health concern of pharmacoresistant epilepsy necessitates innovative therapeutic strategies. Drug resistance often arises due to complex pharmacokinetic challenges. Beta-cyclodextrin, known for enhancing drug solubility and stability, offers a potential solution for improving the efficacy of antiseizure medications. This study aims to investigate the impact of beta-cyclodextrin-complexed rufinamide on seizure-like activity using an in vitro model of temporal lobe epilepsy.
Methods: Seizure-like neuronal activity was induced using a low-magnesium model. Local field potentials were recorded from transverse rat hippocampal slices. Rufinamide was solubilized using beta-cyclodextrin and administered at 100 micromolar concentration. The impact on various seizure-like parameters and time-resolved phase-amplitude coupling was assessed.
Results: Rufinamide increased the duration of the preictal phase while reducing the duration of ictal and postictal phases. The frequency of seizure-like events was higher in rufinamide. No significant change was observed in the firing rate of the first 10 ictal spikes, but the firing frequency of the second set of 10 ictal spikes was higher during rufinamide perfusion. Time-resolved phase-amplitude coupling maximum analysis did not reveal significant differences between the control and rufinamide treatment.
Conclusions: Beta-cyclodextrin-solubilized rufinamide significantly modulates seizure-like event dynamics, exhibiting both anticonvulsant and proconvulsant effects. While the compound shortened seizure-like activity, it increased the frequency of seizure-like events. Our observations suggest a need for further investigation into the solubilization method and its impact on rufinamide’s bioavailability. Dose-dependent effects and underlying molecular mechanisms should also be explored to enhance the pharmacological properties of antiseizure medications.

Effect of carbamazepine-beta-cyclodextrin inclusion complex on seizure-like events in an in vitro model of temporal lobe epilepsy

Rita-Judit Kiss¹, Ágnes Csüdör², Máté Sárosi², Zsolt András Nagy², Ádám Szentes², Zsolt Gáll³, Tibor Szilágyi¹, Károly Orbán-Kis¹

1. Physiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania
2. George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania
3. Pharmacology and Clinical Pharmacy Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania

DOI: 10.2478/amma-2024-0007

Objective: Pharmacoresistant epilepsy represents a significant global health challenge, necessitating novel therapeutic approaches. Despite advances in antiseizure medications, many patients remain treatment-resistant partially due to complex pharmacokinetic issues. Beta-cyclodextrin, known for enhancing drug solubility and stability, offers potential solutions by forming inclusion complexes, thereby improving anti-seizure medication’s efficacy. This study aimed to investigate the effect of beta-cyclodextrin and beta-cyclodextrin-complexed carbamazepine on epileptiform activities, using an in vitro model of temporal lobe epilepsy.
Methods: Seizure-like neuronal activity was induced using the low-magnesium model. Local field potentials were recorded from transverse rat hippocampal slices immersed in epileptogenic artificial cerebrospinal fluid, followed by the administration of either beta-cyclodextrin or carbamazepine, the latter in 100 micromolar concentration.
Results: Beta cyclodextrin, applied alone, significantly reduced the duration of interictal and ictal phases while increasing the frequency of seizure-like events. Carbamazepine exhibited an important anticonvulsant effect, significantly reducing ictal and postictal phase durations. However, the frequency of seizure-like events was increased. Notably, in some of the slices, carbamazepine completely suppressed epileptiform activity.
Conclusions: Beta cyclodextrin had an effect on its own; it shortened seizure durations and increased their frequency. Carbamazepine in complexed form, as used in our study, exhibited anticonvulsant efficacy, emphasizing the feasibility of solubility enhancement by this method. This study provides insights into potential therapeutic strategies for pharmacoresistant temporal lobe epilepsy, improving the pharmacological properties of the drugs. As cyclodextrins emerge as promising excipients for antiepileptic drugs with poor solubility, more effort is needed in order to elucidate the underlying mechanisms of their effects.